Arylamino pyrimidine compound

ABSTRACT

A pyrimidine derivative represented by the formula (II) or (III): ##STR1## (wherein R 1  and R 2  each represent H, a halogen, amino, nitro, an unsubstituted or substituted alkyl, an alkoxy or an alkoxycarbonyl, or R 1  and R 2  are bonded together to form an unsubstituted or substituted alkylene; R 3  represents an aralkyl or a hetero aromatic ring type-alkyl, R 4  represents H or acyl, R 5  represents H, OH or an alkoxy, R 6  represents H, a halogen, an alkyl or an alkoxy, X represents --CH=, --CH=CH--(CH 2 ) p  --, --CH 2  -- or --CH 2  CH 2  --(CH 2 ) p  --, Y represents =CH-- (CH 2 ) p  --, --CH 2  --(CH 2 ) p  --, a single bond or a double bond, p represents 0 or 1, and . . . represents a single bond or a double bond), 
     and a salt thereof have selective acetylcholinesterase-inhibiting activities and selective A type monoamine oxidase-inhibiting activities, and are useful as an antidepressant and an agent for curing senile dementia.

TECHNICAL FIELD

This invention relates to a pyrimidine derivative having both of anexcellent selective acetylcholinesterase-inhibiting activity and anexcellent selective A type monoamine oxidase-inhibiting activity anduseful as an antidepressant and an agent for curing senile dementia, anda salt thereof.

BACKGROUND ART

In senile dementia, acetylcholine in a brain is lacking so that anacetylcholinesterase-inhibiting agent has been studied. For example, asan agent for curing dementia, there have been disclosed1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine, etc. inJapanese Provisional Patent Publication No. 79151/1989 and1-benzyl-4-[2-(4pyrrolidinobenzoyl)ethyl]piperidine, etc. in JapaneseProvisional Patent Publication No. 173867/1991 (U.S. Pat. No.5,177,087). However, senile dementia is generally accompanied withsymptoms such as depression, lowering of volition, etc. so that varioussymptoms of senile dementia cannot be ameliorated sufficiently only byan acetylcholinesterase-inhibiting agent. On the other hand, depressionis related to monoamine (noradrenaline, serotonin), and as anantidepressant having an A type monoamine oxidase-inhibiting activity,there has been known, for example,4-(4-cyanoanilino)-5,6-dihydro-7H-cyclopenta[d]pyrimidine as disclosedin Japanese Provisional Patent Publication No. 203072/1982 (U.S. Pat.No. 4,450,162).

The present inventors have studied for many years in order to develop amedicine having both of a selective acetylcholinesterase-inhibitingactivity and a selective A type monoamine oxidase-inhibiting activityand therefore having a further improved curing effect as an agent forcuring senile dementia, and consequently found that a pyrimidinederivative having a specific structure with selective inhibitingactivities to both enzymes, to accomplish the present invention.

DISCLOSURE OF THE INVENTION

The present invention is a pyrimidine derivative represented by theformula (I): ##STR2##

(wherein R¹ and R² each represent a hydrogen atom, a halogen atom, anamino group, a nitro group, an alkyl group, a lower alkoxy group or alower alkoxycarbonyl group, or R¹ and R² are bonded together to form analkylene group, and said alkyl group and alkylene group may besubstituted by a halogen, hydroxy, a lower alkoxy, a lower alkenyloxy,an aryloxy, an aralkyloxy or an acyloxy.

R³ represents an aralkyl group or a hetero aromatic ring type-alkylgroup and the aryl portion of said aralkyl group and the hetero aromaticring portion of the hetero aromatic ring type-alkyl group may besubstituted by a halogen, amino, alkanoylamino, cyano, nitro, hydroxy, alower alkyl, a lower alkoxy, an aralkyloxy, an alkylenedioxy, ahalogeno-lower alkyl or a halogeno-lower alkoxy.

R⁴ represents a hydrogen atom or an acyl group.

R⁵ represents a hydrogen atom, a hydroxy group or a lower alkoxy group.

A represents ##STR3## where R⁶ represents a hydrogen atom, a halogenatom, a lower alkyl group or a lower alkoxy group, X represents --CH=,--CH=CH--(CH₂)_(p) --, --CH₂ -- or --CH₂ CH₂ --(CH₂)_(p) --, Yrepresents =CH--(CH₂)_(p) --, --CH₂ --(CH₂)_(p) --, a single bond or adouble bond and p represents 0 or 1.

Also, . . . represents a single bond or a double bond, and when . . .represents a double bond or X represents --CH=, or Y represents a doublebond, R⁵ does not exist) and a salt thereof.

The compounds represented by the above formula (I) are roughlyclassified into compounds represented by the following formula (II) andformula (III): ##STR4##

(wherein R¹, R², R³, R⁴, R⁵, R⁶, X, Y and . . . have the same meaningsas defined above)

As the halogen atom of R¹ and R², there may be mentioned fluorine,chlorine, bromine and iodine; as the alkyl group, there may be mentioneda C₁₋₁₀ straight or branched alkyl group such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl, heptyl,octyl, nonyl and decyl; as the lower alkoxy group, there may bementioned a C₁₋₄ straight or branched lower alkoxy group such asmethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy andt-butoxy; as the lower alkoxycarbonyl group, there may be mentioned aC₂₋₅ atkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl and t-butoxycarbonyl; and as the alkylene groupformed by bonding R¹ and R² together, there may be mentioned a C₃₋₆straight or branched alkylene group such as trimethylene, 1-, 2- or3-methyltrimethylene, 1,2-dimethyltrimethylene,2,2-dimethyltrimethylene, 1,3-dimethyltrimethylene, tetramethylene, 1-or 2-methyltetramethylene and 1,2-dimethyltetramethylene.

The above alkyl group and alkylene group may have a substituent(s). Assaid substituent, there may be mentioned a halogen atom such asfluorine, chlorine, bromine and iodine; a hydroxy group; a C₁₋₄ straightor branched lower alkoxy group such as methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy and t-butoxy; a C₃₋₄ loweralkenyloxy group such as allyloxy and 2-butenyloxy; an aryloxy groupsuch as phenoxy and naphthoxy; an aralkyloxy group such as benzyloxy andphenethyloxy; a C₁₋₁₀ aliphatic acyloxy group such as formyloxy,acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy,isovaleryloxy, pivaloyloxy, hexanoyloxy, heptanoyloxy, octanoyloxy,nonanonyloxy and decanoyloxy; an aromatic aliphatic acyloxy group suchas phenylacetoxy and cinnamoyloxy; and an aromatic acyloxy group such asbenzoyloxy and naphthoyloxy.

As the groups of R¹ and R², preferred are a hydrogen atom, a fluorineatom, a chlorine atom, a bromine atom, a C₁₋₇ straight or branched alkylgroup, a trimethylene group, a tetramethylene group and a2,2-dimethyltrimethylene group, and as the group having asubstituent(s), preferred are a hydroxymethyl group, a fluoromethylgroup, a chloromethyl group, a bromomethyl group, a methoxymethyl group,a phenoxymethyl group, a benzyloxymethyl group, an acetoxymethyl group,a propionyloxymethyl group, a benzoyloxymethyl group, a 1- or2-hydroxyethyl group, a 1- or 2-fluoroethyl group, a 1- or3-hydroxytrimethylene group, a 1- or 3-fluorotrimethylene group, a 1- or3-chlorotrimethylene group, a 1- or 3-bromotrimethylene group, a 1- or3-methoxytrimethylene group, a 1- or 3-phenoxytrimethylene group, a 1-or 3-acetoxytrimethylene group, a 1,3-dihydroxytrimethylene group and a1,3-difluorotrimethylene group. As the groups of R¹ and R², particularlypreferred are a hydrogen atom, a fluorine atom, a chlorine atom, abromine atom, a methyl group, an ethyl group, a propyl group, anisopropyl group, a butyl group, a trimethylene group, a tetramethylenegroup and a 2,2-dimethyltrimethylene group, and as the group having asubstituent(s), particularly preferred are a hydroxymethyl group, afluoromethyl group, a methoxymethyl group, an acetoxymethyl group, a 1-or 3-hydroxytrimethylene group, a 1- or 3-fluorotrimethylene group, a 1-or 3-methoxytrimethylene group, a 1- or 3-acetoxytrimethylene group anda 1,3-difluorotrimethylene group. It is particularly preferred that R¹and R² form a trimethylene group or a tetramethylene group incombination, or one is a C₁₋₄ alkyl group and the other is a hydrogenatom, a chlorine atom or a C₁₋₄ alkyl group, and most preferred is acompound wherein R¹ and R² form a trimethylene group in combination orR¹ is a C₁₋₄ alkyl group and R² is a hydrogen atom or a C₁₋₄ alkylgroup.

As the aralkyl group of R³, there may be mentioned an aryl C₁₋₄ alkylgroup such as benzyl, phenethyl, sec-phenethyl, phenylpropyl,phenylbutyl, naphthylmethyl and diphenylmethyl; and as the heteroaromatic ring type-alkyl group, there may be mentioned a hetero aromaticring type-C₁₋₄ alkyl group such as thienylmethyl, thienylethyl,thienylpropyl, thienylbutyl, furylmethyl, pyridylmethyl,pyrimidinylmethyl, thiazolylmethyl, oxazolylmethyl, imidazolylmethyl,2-benzothiazolylmethyl, 2-benzoxazolylmethyl and2-benzoimidazolylmethyl. The aryl portion of the above aralkyl group andthe hetero aromatic ring portion of the hetero aromatic ring type-alkylgroup may have a substituent(s), and as said substituent, there may bementioned a halogen atom such as fluorine, chlorine, bromine and iodine;a C₁₋₄ straight or branched lower alkyl group such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl; a C₁₋₄straight or branched lower alkoxy group such as methoxy, ethoxy,propoxy, iso-propoxy, butoxy, isobutoxy, sec-butoxy and t-butoxy; anaralkyloxy group such as benzyloxy, phenethyloxy and naphthylmethoxy; analkylenedioxy group such as methylenedioxy and ethylenedioxy; an aminogroup, a C₁₋₄ alkanoylamino such as formylamino, acetylamino,propionylamino, butyrylamino and isobutyrylamino; a nitro group; a cyanogroup; a hydroxy group; a C₁₋₄ halogeno-lower alkyl group such asfluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl,2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2,2-trifluoroethyl,3-fluoropropyl and 4-fluorobutyl; and a C₁₋₄ halogeno-lower alkoxy groupsuch as fluoromethoxy, difluoromethoxy, trifluoromethoxy,2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2,2-trifluoroethoxy,3-fluoropropoxy and 4-fluorobutoxy.

As the group of R³, preferred are a benzyl group, a sec-phenethyl group,a fluorobenzyl group, a methoxybenzyl group, an ethylenedioxybenzylgroup, a hydroxybenzyl group, a chlorobenzyl group, a methylbenzylgroup, a trifluoromethylbenzyl group, an aminobenzyl group, anacetylaminobenzyl group, a nitrobenzyl group, a cyanobenzyl group, adiphenylmethyl group, a di(4-fluorophenyl)methyl group, a thienylmethylgroup, a furylmethyl group, a pyridylmethyl group, a methylpyridylmethylgroup and a pyrimidinylmethyl group. As the group of R³, particularlypreferred are a benzyl group, a sec-phenethyl group, a 2-, 3- or4-fluorobenzyl group, a 2-, 3- or 4-chlorobenzyl group, a 2-, 3- or4-methoxybenzyl group, a 2-, 3- or 4-cyanobenzyl group, a 2-, 3- or4-nitrobenzyl group, a 2-thienylmethyl group, a 2-furylmethyl group, a2-pyridylmethyl group and a 6-methyl-2-pyridylmethyl group.

As the acyl group of R⁴, there may be mentioned a C₁₋₁₀ aliphatic acylgroup such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, nonanoyl anddecanoyl; an aromatic aliphatic acyl group such as phenylacetyl andcinnamoyl; and an aromatic acyl group such as benzoyl and naphthoyl.

As the group of R⁴, preferred are a hydrogen atom, a formyl group, anacetyl group, a propionyl group, a butyryl group and a pivaloyl group,and particularly preferred are a hydrogen atom and an acetyl group.

As the lower alkoxy group of R⁵, the same lower alkoxy group mentionedin R¹ and R² may be mentioned.

As the group of R⁵, preferred are a hydrogen atom, a hydroxy group, amethoxy group and an ethoxy group, and particularly preferred is ahydrogen atom.

As the halogen atom and the lower alkoxy group of R⁶, the same halogenatom and lower alkoxy group mentioned in R¹ and R² may be mentioned; andas the lower alkyl group, there may be mentioned a C₁₋₄ straight orbranched alkyl group such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl and sec-butyl.

As the group of R⁶, preferred are a hydrogen atom, a fluorine atom, achlorine atom, a methyl group and a methoxy group, and particularlypreferred are a hydrogen atom, a fluorine atom, a chlorine atom and amethoxy group.

As X in the formula (II), --CH=, --CH₂ --, --CH₂ CH₂ -- and --CH=CH--are particularly preferred. As Y in the formula (III), --CH₂ -- and=CH-- are particularly preferred. The compound of the formula (II) ispreferred for achieving the object of the present invention.

The . . . is preferably a single bond.

The compounds of the formula (I), the formula (II) and the formula (III)may be converted into salts, if necessary. As a pharmaceuticallyacceptable salt, there may be mentioned a salt of a mineral acid such ashydrochloride, hydrobromide, hydroiodide, sulfate and phosphate; asulfonate such as methanesulfonate, ethanesulfonate, benzenesulfonateand p-toluenesulfonate; oxalate, maleate, fumarate and tartrate; and anacid addition salt of an organic acid such as citrate. The compounds ofthe formula (I), the formula (II) and the formula (III) or salts thereofmay exist as hydrates.

Examples of the compound of the formula (II) are shown in Table 1(Compound II), and examples of the compound of the formula (III) areshown in Table 2 (Compound III), respectively.

                                      TABLE 1                                     __________________________________________________________________________    (Compound II)                                                                  ##STR5##                                                                         ##STR6##                                                                                   ##STR7##                                                                              ##STR8##                                                                              ##STR9##                                                                           ##STR10##                                                                               ##STR11##                                                                                ##STR12##          __________________________________________________________________________     1 CH.sub.2 CH.sub.2 CH.sub.2                                                                         H       H    CH.sub.2                                                                                 ##STR13## benzyl               2 "                    "       "    (CH.sub.2).sub.2                                                                        "          "                    3 "                    "       "    (CH.sub.2).sub.3                                                                        "          "                    4 "                    "       "    CH                                                                                       ##STR14## "                    5 "                    "       "    CHCH                                                                                     ##STR15## "                    6 "                    "       "    CHCHCH.sub.2                                                                            "          "                    7 "                    "       "    CH.sub.2  "          4-fluoro-                                                                     benzyl               8 "                    "       "    (CH.sub.2).sub.2                                                                        "          4-fluoro-                                                                     benzyl               9 "                    "       "    (CH.sub.2).sub.3                                                                        "          4-fluoro-                                                                     benzyl               10                                                                              "                    "       "    CH                                                                                       ##STR16## 4-fluoro-                                                                     benzyl               11                                                                              "                    "       "    CHCH                                                                                     ##STR17## 4-fluoro-                                                                     benzyl               12                                                                              "                    "       "    CHCHCH.sub.2                                                                            "          4-fluoro-                                                                     benzyl               13                                                                              "                    "       "    CH.sub.2  "          3-fluoro-                                                                     benzyl               14                                                                              "                    "       "    (CH.sub.2).sub.2                                                                        "          3-fluoro-                                                                     benzyl               15                                                                              "                    "       "    (CH.sub.2).sub.3                                                                        "          3-fluoro-                                                                     benzyl               16                                                                              "                    "       "    CH                                                                                       ##STR18## 3-fluoro-                                                                     benzyl               17                                                                              "                    "       "    CHCH                                                                                     ##STR19## 3-fluoro-                                                                     benzyl               18                                                                              "                    "       "    CHCHCH.sub.2                                                                            "          3-fluoro-                                                                     benzyl               19                                                                              CH.sub.2 CH.sub.2 CH.sub.2                                                                         H       H    CH.sub.2                                                                                 ##STR20## 2-fluoro-                                                                     benzyl               20                                                                              "                    "       "    (CH.sub.2).sub.2                                                                        "          2-fluoro-                                                                     benzyl               21                                                                              "                    "       "    (CH.sub.2).sub.3                                                                        "          2-fluoro-                                                                     benzyl               22                                                                              "                    "       "    CH                                                                                       ##STR21## 2-fluoro-                                                                     benzyl               23                                                                              "                    "       "    CHCH                                                                                     ##STR22## 2-fluoro-                                                                     benzyl               24                                                                              "                    "       "    CHCHCH.sub.2                                                                            "          2-fluoro-                                                                     benzyl               25                                                                              "                    "       "    CH.sub.2  "          4-meth-                                                                       oxy-                                                                          benzyl               26                                                                              "                    "       "    (CH.sub.2).sub.2                                                                        "          4-meth-                                                                       oxy-                                                                          benzyl               27                                                                              "                    "       "    (CH.sub.2).sub.3                                                                        "          4-meth-                                                                       oxy-                                                                          benzyl               28                                                                              "                    "       "    CH                                                                                       ##STR23## 4-meth- oxy-                                                                  benzyl               29                                                                              "                    "       "    CHCH                                                                                     ##STR24## 4-meth- oxy-                                                                  benzyl               30                                                                              "                    "       "    CHCHCH.sub.2                                                                            "          4-meth-                                                                       oxy-                                                                          benzyl               31                                                                              "                    "       "    CH.sub.2  "          3-meth-                                                                       oxy-                                                                          benzyl               32                                                                              "                    "       "    (CH.sub.2).sub.2                                                                        "          3-meth-                                                                       oxy-                                                                          benzyl               33                                                                              "                    "       "    (CH.sub.2).sub.3                                                                        "          3-meth-                                                                       oxy-                                                                          benzyl               34                                                                              "                    "       "    CH                                                                                       ##STR25## 3-meth- oxy-                                                                  benzyl               35                                                                              "                    "       "    CHCH                                                                                     ##STR26## 3-meth- oxy-                                                                  benzyl               36                                                                              "                    "       "    CHCHCH.sub.2                                                                            "          3-meth-                                                                       oxy-                                                                          benzyl               37                                                                              "                    "       "    CH.sub.2  "          2-meth-                                                                       oxy-                                                                          benzyl               38                                                                              CH.sub.2 CH.sub.2 CH.sub.2                                                                         H       H    (CH.sub.2).sub.2                                                                         ##STR27## 2-meth- oxy-                                                                  benzyl               39                                                                              "                    "       "    (CH.sub.2).sub.3                                                                        "          2-meth-                                                                       oxy-                                                                          benzyl               40                                                                              "                    "       "    CH                                                                                       ##STR28## 2-meth- oxy-                                                                  benzyl               41                                                                              "                    "       "    CHCH                                                                                     ##STR29## 2-meth- oxy-                                                                  benzyl               42                                                                              "                    "       "    CHCHCH.sub.2                                                                            "          2-meth-                                                                       oxy-                                                                          benzyl               43                                                                              "                    "       "    CH.sub.2  "          4-                                                                            hydroxy-                                                                      benzyl               44                                                                              "                    "       "    (CH.sub.2).sub.2                                                                        "          4-                                                                            hydroxy-                                                                      benzyl               45                                                                              "                    "       "    (CH.sub.2).sub.3                                                                        "          4-                                                                            hydroxy-                                                                      benzyl               46                                                                              "                    "       "    CH                                                                                       ##STR30## 4- hydroxy-                                                                   benzyl               47                                                                              "                    "       "    CHCH                                                                                     ##STR31## 4- hydroxy-                                                                   benzyl               48                                                                              "                    "       "    CHCHCH.sub.2                                                                            "          4-                                                                            hydroxy-                                                                      benzyl               49                                                                              "                    "       "    CH.sub.2  "          4-chloro-                                                                     benzyl               50                                                                              "                    "       "    (CH.sub.2).sub.2                                                                        "          4-chloro-                                                                     benzyl               51                                                                              "                    "       "    (CH.sub.2).sub.3                                                                        "          4-chloro-                                                                     benzyl               52                                                                              "                    "       "    CH                                                                                       ##STR32## 4-chloro-                                                                     benzyl               53                                                                              "                    "       "    CHCH                                                                                     ##STR33## 4-chloro-                                                                     benzyl               54                                                                              "                    "       "    CHCHCH.sub.2                                                                            "          4-chloro-                                                                     benzyl               55                                                                              "                    "       "    CH.sub.2  "          3-chloro-                                                                     benzyl               56                                                                              "                    "       "    (CH.sub.2).sub.2                                                                        "          3-chloro-                                                                     benzyl               57                                                                              CH.sub.2 CH.sub.2 CH.sub.2                                                                         H       H    (CH.sub.2).sub.3                                                                         ##STR34## 3-chloro-                                                                     benzyl               58                                                                              "                    "       "    CH                                                                                       ##STR35## 3-chloro-                                                                     benzyl               59                                                                              "                    "       "    CHCH                                                                                     ##STR36## 3-chloro-                                                                     benzyl               60                                                                              "                    "       "    CHCHCH.sub.2                                                                            "          3-chloro-                                                                     benzyl               61                                                                              "                    "       "    CH.sub.2  "          2-chloro-                                                                     benzyl               62                                                                              "                    "       "    (CH.sub.2).sub.2                                                                        "          2-chloro-                                                                     benzyl               63                                                                              "                    "       "    (CH.sub.2).sub.3                                                                        "          2-chloro-                                                                     benzyl               64                                                                              "                    "       "    CH                                                                                       ##STR37## 2-chloro-                                                                     benzyl               65                                                                              "                    "       "    CHCH                                                                                     ##STR38## 2-chloro-                                                                     benzyl               66                                                                              "                    "       "    CHCHCH.sub.2                                                                            "          2-chloro-                                                                     benzyl               67                                                                              "                    "       "    CH.sub.2  "          4-methyl-                                                                     benzyl               68                                                                              "                    "       "    (CH.sub.2).sub.2                                                                        "          4-methyl-                                                                     benzyl               69                                                                              "                    "       "    (CH.sub.2).sub.3                                                                        "          4-methyl-                                                                     benzyl               70                                                                              "                    "       "    CH                                                                                       ##STR39## 4-methyl-                                                                     benzyl               71                                                                              "                    "       "    CHCH                                                                                     ##STR40## 4-methyl-                                                                     benzyl               72                                                                              "                    "       "    CHCHCH.sub.2                                                                            "          4-methyl-                                                                     benzyl               73                                                                              "                    "       "    CH.sub.2  "          4-nitro-                                                                      benzyl               74                                                                              "                    "       "    (CH.sub.2).sub.2                                                                        "          4-nitro-                                                                      benzyl               75                                                                              "                    "       "    (CH.sub.2).sub.3                                                                        "          4-nitro-                                                                      benzyl               76                                                                              CH.sub.2 CH.sub.2 CH.sub.2                                                                         H       H    CH                                                                                       ##STR41## 4-nitro-                                                                      benzyl               77                                                                              "                    "       "    CHCH                                                                                     ##STR42## 4-nitro-                                                                      benzyl               78                                                                              "                    "       "    CHCHCH.sub.2                                                                            "          4-nitro-                                                                      benzyl               79                                                                              "                    "       "    CH.sub.2  "          4-tri-                                                                        fluoro-                                                                       methyl-                                                                       benzyl               80                                                                              "                    "       "    (CH.sub.2).sub.2                                                                        "          4-tri-                                                                        fluoro-                                                                       methyl-                                                                       benzyl               81                                                                              "                    "       "    CH                                                                                       ##STR43## 4-tri- fluoro-                                                                methyl- benzyl       82                                                                              "                    "       "    (CH.sub.2).sub.3                                                                         ##STR44## 4-tri- fluoro-                                                                methyl- benzyl       83                                                                              "                    "       "    CHCH      "          4-tri-                                                                        fluoro-                                                                       methyl-                                                                       benzyl               84                                                                              "                    "       "    CHCHCH.sub.2                                                                            "          4-tri-                                                                        fluoro-                                                                       methyl-                                                                       benzyl               85                                                                              "                    "       "    CH.sub.2  "          sec-phen-                                                                     ethyl                86                                                                              "                    "       "    (CH.sub.2).sub.2                                                                        "          sec-phen-                                                                     ethyl                87                                                                              "                    "       "    (CH.sub.2).sub.3                                                                        "          sec-phen-                                                                     ethyl                88                                                                              "                    "       "    CH                                                                                       ##STR45## sec-phen-                                                                     ethyl                89                                                                              "                    "       "    CHCH                                                                                     ##STR46## sec-phen-                                                                     ethyl                90                                                                              "                    "       "    CHCHCH.sub.2                                                                            "          sec-phen-                                                                     ethyl                91                                                                              "                    "       "    CH.sub.2  "          diphenyl-                                                                     methyl               92                                                                              "                    "       "    (CH.sub.2).sub.2                                                                        "          diphenyl-                                                                     methyl               93                                                                              "                    "       "    (CH.sub.2).sub.3                                                                        "          diphenyl-                                                                     methyl               94                                                                              "                    "       "    CH                                                                                       ##STR47## diphenyl-                                                                     methyl               95                                                                              CH.sub.2 CH.sub.2 CH.sub.2                                                                         H       H    CHCH                                                                                     ##STR48## diphenyl-                                                                     methyl               96                                                                              "                    "       "    CHCHCH.sub.2                                                                            "          diphenyl-                                                                     methyl               97                                                                              "                    "       "    CH.sub.2  "          di(4-                                                                         fluoro-                                                                       phenyl)-                                                                      methyl               98                                                                              "                    "       "    (CH.sub.2).sub.2                                                                        "          di(4-                                                                         fluoro-                                                                       phenyl)-                                                                      methyl               99                                                                              "                    "       "    (CH.sub.2).sub.3                                                                        "          di(4-                                                                         fluoro-                                                                       phenyl)-                                                                      methyl              100                                                                              "                    "       "    CH                                                                                       ##STR49## di(4- fluoro-                                                                 phenyl)-                                                                      methyl              101                                                                              "                    "       "    CHCH                                                                                     ##STR50## di(4- fluoro-                                                                 phenyl)-                                                                      methyl              102                                                                              "                    "       "    CHCHCH.sub.2                                                                            "          di(4-                                                                         fluoro-                                                                       phenyl)-                                                                      methyl              103                                                                              "                    "       "    CH.sub.2  "          2-thienyl-                                                                    methyl              104                                                                              "                    "       "    (CH.sub.2).sub.2                                                                        "          2-thienyl-                                                                    methyl              105                                                                              "                    "       "    (CH.sub.2).sub.3                                                                        "          2-thienyl-                                                                    methyl              106                                                                              "                    "       "    CH                                                                                       ##STR51## 2-thienyl-                                                                    methyl              107                                                                              "                    "       "    CHCH                                                                                     ##STR52## 2-thienyl-                                                                    methyl              108                                                                              "                    "       "    CHCHCH.sub.2                                                                            "          2-thienyl-                                                                    methyl              109                                                                              "                    "       "    CH.sub.2  "          2-                                                                            pyridyl-                                                                      methyl              110                                                                              "                    "       "    (CH.sub.2).sub.2                                                                        "          2-                                                                            pyridyl-                                                                      methyl              111                                                                              "                    "       "    (CH.sub.2).sub.2                                                                        "          2-                                                                            pyridyl-                                                                      methyl              112                                                                              "                    "       "    CH                                                                                       ##STR53## 2- pyridyl-                                                                   methyl              113                                                                              CH.sub.2 CH.sub.2 CH.sub.2                                                                         H       H    CHCH                                                                                     ##STR54## 2- pyridyl-                                                                   methyl              114                                                                              "                    "       "    CHCHCH.sub.2                                                                            "          2-                                                                            pyridyl-                                                                      methyl              115                                                                              "                    "       "    CH.sub.2  "          4-                                                                            pyridyl-                                                                      methyl              116                                                                              "                    "       "    (CH.sub.2).sub.2                                                                        "          4-                                                                            pyridyl-                                                                      methyl              117                                                                              "                    "       "    (CH.sub.2).sub.3                                                                        "          4-                                                                            pyridyl-                                                                      methyl              118                                                                              "                    "       "    CH                                                                                       ##STR55## 4- pyridyl-                                                                   methyl              119                                                                              "                    "       "    CHCH                                                                                     ##STR56## 4- pyridyl-                                                                   methyl              120                                                                              "                    "       "    CHCHCH.sub.2                                                                            "          4-                                                                            pyridyl-                                                                      methyl              121                                                                              "                    "       "    CH.sub.2  "          2-pyr-                                                                        imidinyl-                                                                     methyl              122                                                                              "                    "       "    (CH.sub.2).sub.2                                                                        "          2-pyr-                                                                        imidinyl-                                                                     methyl              123                                                                              "                    "       "    (CH.sub.2).sub.3                                                                        "          2-pyr-                                                                        imidinyl-                                                                     methyl              124                                                                              "                    "       "    CH                                                                                       ##STR57## 2-pyr- imidinyl-                                                               methyl             125                                                                              "                    "       "    CHCH                                                                                     ##STR58## 2-pyr- imidinyl-                                                               methyl             126                                                                              "                    "       "    CHCHCH.sub.2                                                                            "          2-pyr-                                                                        imidinyl-                                                                     methyl              127                                                                              "                    "       "    CH.sub.2  "          4-pyr-                                                                        imidinyl-                                                                     methyl              128                                                                              "                    "       "    (CH.sub.2).sub.2                                                                        "          4-pyr-                                                                        imidinyl-                                                                     methyl              129                                                                              "                    "       "    (CH.sub.2).sub.3                                                                        "          4-pyr-                                                                        imidinyl-                                                                     methyl              130                                                                              "                    "       "    CH                                                                                       ##STR59## 4-pyr- imidinyl-                                                               methyl             131                                                                              "                    "       "    CHCH                                                                                     ##STR60## 4-pyr- imidinyl-                                                               methyl             132                                                                              CH.sub.2 CH.sub.2 CH.sub.2                                                                         H       H    CHCHCH.sub.2                                                                             ##STR61## 4-pyr- imidinyl-                                                               methyl             133                                                                              "                    "       "    (CH.sub.2).sub.2                                                                        "          4-di-                                                                         fluoro-                                                                       methoxy-                                                                      benzyl              134                                                                              "                    "       "    "         "          3-di-                                                                         fluoro-                                                                       methoxy-                                                                      benzyl              135                                                                              "                    "       "    "         "          2-di-                                                                         fluoro-                                                                       methoxy-                                                                      benzyl              136                                                                              H            H       "       "    (CH.sub.2).sub.2                                                                        "          benzyl              137                                                                              "            CH.sub.3                                                                              "       "    "         "          "                   138                                                                              "            C.sub.2 H.sub.5                                                                       "       "    "         "          "                   139                                                                              "            C.sub.3 H.sub.7                                                                       "       "    "         "          "                   140                                                                              "            i-C.sub.3 H.sub.7                                                                     "       "    "         "          "                   141                                                                              "            C.sub.4 H.sub.9                                                                       "       "    "         "          "                   142                                                                              "            sec-C.sub.4 H.sub.9                                                                   "       "    "         "          "                   143                                                                              "            C.sub.6 H.sub.13                                                                      "       "    "         "          "                   144                                                                              "            C.sub.8 H.sub.17                                                                      "       "    "         "          "                   145                                                                              "            C.sub.10 H.sub.21                                                                     "       "    "         "          "                   146                                                                              "            Cl      "       "    "         "          "                   147                                                                              "            Br      "       "    "         "          "                   148                                                                              "            OCH.sub.3                                                                             "       "    "         "          "                   149                                                                              "            OC.sub.2 H.sub.5                                                                      "       "    "         "          "                   150                                                                              CH.sub.3     CH.sub.3                                                                              H       H    (CH.sub.2).sub.2                                                                         ##STR62## benzyl              151                                                                              C.sub.2 H.sub.5                                                                            "       "       "    "         "          "                   152                                                                              C.sub.3 H.sub.7                                                                            "       "       "    "         "          "                   153                                                                              i-C.sub.3 H.sub.7                                                                          "       "       "    "         "          "                   154                                                                              C.sub.4 H.sub.9                                                                            "       "       "    "         "          "                   155                                                                              sec-C.sub.4 H.sub.9                                                                        "       "       "    "         "          "                   156                                                                              i-C.sub.4 H.sub.9                                                                          "       "       "    "         "          "                   157                                                                              C.sub.5 H.sub.11                                                                           "       "       "    "         "          "                   158                                                                              C.sub.7 H.sub.15                                                                           "       "       "    "         "          "                   159                                                                              C.sub.9 H.sub.19                                                                           "       "       "    "         "          "                   160                                                                              Cl           "       "       "    "         "          "                   161                                                                              Br           "       "       "    "         "          "                   162                                                                              Cl           "       "       "    CHCH      "          "                   163                                                                              CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                                "       "    (CH.sub.2).sub.2                                                                        "          "                   164                                                                              CH(CH.sub.3)CH.sub.2 CH.sub.2                                                                      "       "    "         "          "                   165                                                                              CH.sub.2 CH(CH.sub.3)CH.sub.2                                                                      "       "    "         "          "                   166                                                                              CH.sub.2 CH.sub.2 CH(CH.sub.3)                                                                     "       "    "         "          "                   167                                                                              CH.sub.2 CH.sub.2 CH(OH)                                                                           "       "    "         "          "                   168                                                                              CH.sub.2 CH.sub.2 CH(OCH.sub.3)                                                                    "       "    "         "          "                   169                                                                              CH.sub.2 CH.sub.2 CH(OC.sub.2 H.sub.5)                                                             H       H    (CH.sub.2).sub.2                                                                         ##STR63## benzyl              170                                                                              CH.sub.2 CH.sub.2 CH(OC.sub.3 H.sub.7)                                                             "       "    "         "          "                   171                                                                              CH.sub.2 CH.sub.2 CH(OCH.sub.2 CHCH.sub.2)                                                         "       "    "         "          "                   172                                                                              CH.sub.2 CH.sub.2 CH(OCH.sub.2 C.sub.6 H.sub.5)                                                    "       "    "         "          "                   173                                                                              CH.sub.2 CH.sub.2 CH(OCH.sub.3)                                                                    "       "    CHCH      "          "                   174                                                                              CH.sub.2 CH.sub.2 CH(OCOH)                                                                         "       "    (CH.sub.2).sub.2                                                                        "          "                   175                                                                              CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                                "       "    CHCH      "          "                   176                                                                              CH.sub.2 CH.sub.2 CH(OCOCH.sub.3)                                                                  "       "    (CH.sub.2).sub.2                                                                        "          "                   177                                                                              CH.sub.2 CH.sub.2 CH(OCOC.sub.2 H.sub.5)                                                           "       "    "         "          "                   178                                                                              CH.sub.2 CH.sub.2 CH(OCOC.sub.3 H.sub.7)                                                           "       "    "         "          "                   179                                                                              CH.sub.2 CH.sub.2 CH(OCOC.sub.5 H.sub.11)                                                          "       "    "         "          "                   180                                                                              CH.sub.2 CH.sub.2 CH(OCOC.sub.9 H.sub.19)                                                          "       "    "         "          "                   181                                                                              CH.sub.2 CH.sub.2 CH(OCOCH.sub.2 C.sub.6 H.sub.5)                                                  "       "    "         "          "                   182                                                                              CH.sub.2 CH.sub.2 CH(OCOC.sub.6 H.sub.5)                                                           "       "    "         "          "                   183                                                                              CH.sub.2 CH.sub.2 CH(F)                                                                            "       "    "         "          "                   184                                                                              CH.sub.2 CH.sub.2 CH(Cl)                                                                           "       "    "         "          "                   185                                                                              CH.sub.2 CH.sub.2 CH(Br)                                                                           "       "    "         "          "                   186                                                                              CH.sub.2 CH.sub.2 C(F).sub.2                                                                       "       "    "         "          "                   187                                                                              CH(Br)CH.sub.2 CH(Br)                                                                              "       "    "         "          "                   188                                                                              CH.sub.2 CH.sub.2 CH(F)                                                                            H       H    CHCH                                                                                     ##STR64## benzyl              189                                                                              CH.sub.3     H       "       "    (CH.sub.2).sub.2                                                                        "          "                   190                                                                              "            Cl      "       "    "         "          "                   191                                                                              "            Br      "       "    "         "          "                   192                                                                              "            CH.sub.2 OH                                                                           "       "    "         "          "                   193                                                                              "            CH.sub.2 OCH.sub.3                                                                    "       "    "         "          "                   194                                                                              "            CH.sub.2 OCOCH.sub.3                                                                  "       "    "         "          "                   195                                                                              "            CH.sub.2 F                                                                            "       "    "         "          "                   196                                                                              "            CH.sub.2 Cl                                                                           "       "    "         "          "                   197                                                                              C.sub.2 H.sub.5                                                                            H       "       "    "         "          2-pyr-                                                                        imidinyl-                                                                     methyl              198                                                                              CH.sub.2 C(CH.sub.3).sub.2 CH.sub.2                                                                "       "    "         "          benzyl              199                                                                              CH.sub.3     CH.sub.3                                                                              "       "    CHCH      "          "                   200                                                                              C.sub.2 H.sub.5                                                                            C.sub.2 H.sub.5                                                                       "       "    "         "          "                   201                                                                              CH.sub.2 C(CH.sub.3).sub.2 CH.sub.2                                                                "       "    "         "          "                   202                                                                              CH.sub.3     H       "       "    "         "          "                   203                                                                              C.sub.2 H.sub.5                                                                            "       "       "    "         "          "                   204                                                                              C.sub.3 H.sub.7                                                                            "       "       "    "         "          "                   205                                                                              C.sub.2 H.sub.5                                                                            "       "       "    (CH.sub.2).sub.2                                                                        "          "                   206                                                                              C.sub.3 H.sub.7                                                                            "       "       "    "         "          "                   207                                                                              CH.sub.2 CH.sub.2 CH(OC.sub.6 H.sub.5)                                                             H       H    (CH.sub.2).sub.2                                                                         ##STR65## benzyl              208                                                                              CH.sub.2 CH.sub.2 CH(O-1-C.sub.10 H.sub.7 )                                                        "       "    "         "          "                   209                                                                              CH.sub.2 CH.sub.2 CH.sub.2                                                                         "       "    CHCH      "          3-                                                                            pyridyl-                                                                      methyl              210                                                                              "                    "       "    (CH.sub.2).sub.2                                                                        "          3-                                                                            pyridyl-                                                                      methyl              211                                                                              "                    "       "    CHCH      "          2-methyl-                                                                     benzyl              212                                                                              "                    "       "    (CH.sub.2).sub.2                                                                        "          2-methyl-                                                                     benzyl              213                                                                              "                    "       "    CHCH      "          3-methyl-                                                                     benzyl              214                                                                              "                    "       "    (CH.sub.2).sub.2                                                                        "          3-methyl-                                                                     benzyl              215                                                                              "                    "       "    CH.sub.2                                                                                 ##STR66## benzyl              216                                                                              "                    "       "    "                                                                                        ##STR67## "                   217                                                                              "                    "       "    "                                                                                        ##STR68## "                   218                                                                              "                    "       "    (CH.sub.2).sub.2                                                                         ##STR69## 4-cyano-                                                                      benzyl              219                                                                              CH.sub.3     H       "       "    CH.sub.2  "          2-                                                                            pyridyl-                                                                      methyl              220                                                                              "            "       "       "    "         "          benzyl              221                                                                              CH.sub.2 CH.sub.2 CH.sub.2                                                                         COCH.sub.3                                                                            "    (CH.sub.2).sub.2                                                                        "          "                   222                                                                              COOC.sub.2 H.sub.5                                                                         H       H       "    "         "          "                   223                                                                              C.sub.2 H.sub.5                                                                            C.sub.2 H.sub.5                                                                       "       "    "         "          "                   224                                                                              CH.sub.2 CH.sub.2 CH.sub.2                                                                         "       "    "         "          1-                                                                            naphthyl-                                                                     methyl              225                                                                              "                    "       "    "         "          3-cyano-                                                                      benzyl              226                                                                              CH.sub.3     H       H       2-F  CH.sub.2                                                                                 ##STR70## benzyl              227                                                                              "            "       "       3-F  "         "          "                   228                                                                              "            "       "       3-Cl "         "          "                   229                                                                              Cl           "       "       H    (CH.sub.2).sub.2                                                                        "          "                   230                                                                              Br           "       "       "    "         "          "                   231                                                                              CH.sub.2 CH.sub.2 CH.sub.2                                                                         "       "    "         "          3,4-                                                                          methyl-                                                                       ene-                                                                          dioxy-                                                                        benzyl              232                                                                              "                    "       "    "         "          3-tri-                                                                        fluoro-                                                                       methyl-                                                                       benzyl              233                                                                              "                    "       "    "         "          2,3-di-                                                                       methoxy-                                                                      benzyl              234                                                                              CH.sub.3     CH.sub.3                                                                              "       "    CH.sub.2  "          benzyl              235                                                                              CH.sub.2 CH.sub.2 CH.sub.2                                                                         "       "    (CH.sub.2).sub.2                                                                        "          3,4-                                                                          ethylene-                                                                     dioxy-                                                                        benzyl              236                                                                              CH.sub.2 CH.sub.2 CH(OH)                                                                           "       "    CH.sub.2  "          benzyl              237                                                                              CH.sub.2 CH.sub.2 CH(OCOCH.sub.3)                                                                  "       "    "         "          "                   238                                                                              CH.sub.2 CH.sub.2 CH.sub.2                                                                         "       "    (CH.sub.2).sub.2                                                                        "          6-                                                                            methyl-2-                                                                     pyridyl-                                                                      methyl              239                                                                              "                    "       "    "         "          3-benzyl-                                                                     oxy-                                                                          benzyl              240                                                                              NO.sub.2     OCH.sub.3                                                                             "       "    "         "          benzyl              241                                                                              NH.sub.2     Cl      "       "    "         "          "                   242                                                                              CH.sub.2 CH.sub.2 CH.sub.2                                                                         H       H    (CH.sub.2).sub.2                                                                         ##STR71## 2-nitro-                                                                      benzyl              243                                                                              "                    "       "    "         "          3-nitro-                                                                      benzyl              244                                                                              "                    "       "    "         "          3-amino-                                                                      benzyl              245                                                                              "                    "       2-OCH.sub.3                                                                        CH.sub.2  "          benzyl              246                                                                              CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                                "       "    "         "          "                   247                                                                              CH.sub.2 CH.sub.2 CH.sub.2                                                                         "       2-Cl "         "          "                   248                                                                              CH.sub.3     H       "       H    (CH.sub.2).sub.2                                                                        "          2-                                                                            pyridyl-                                                                      methyl              249                                                                              CH.sub.2 CH.sub.2 CH.sub.2                                                                         "       "    "         "          2-acetyl-                                                                     amino-                                                                        benzyl              250                                                                              CH.sub.3     H       "       2-CH.sub.3                                                                         CH.sub.2  "          benzyl              251                                                                              "            "       "       3-CH.sub.3                                                                         "         "          "                   252                                                                              C.sub.2 H.sub.5                                                                            "       "       H    "         "          "                   253                                                                              C.sub.3 H.sub.7                                                                            "       "       "    "         "          "                   254                                                                              i-C.sub.3 H.sub.7                                                                          "       "       "    "         "          "                   255                                                                              C.sub.4 H.sub.9                                                                            "       "       "    "         "          "                   256                                                                              sec-C.sub.4 H.sub.9                                                                        "       "       "    "         "          "                   257                                                                              i-C.sub.4 H.sub.9                                                                          "       "       "    "         "          "                   258                                                                              CH.sub.3     "       "       "    "         "          2-thienyl-                                                                    methyl              259                                                                              "            "       "       "    "         "          3-thienyl-                                                                    methyl              260                                                                              "            "       "       "    "         "          2-furyl-                                                                      methyl              261                                                                              CH.sub.3     H       H       H    CH.sub.2                                                                                 ##STR72## 3-furyl-                                                                      methyl              262                                                                              "            "       "       "    "         "          3-                                                                            pyridyl-                                                                      methyl              263                                                                              "            "       "       "    "         "          4-                                                                            pyridyl-                                                                      methyl              264                                                                              "            "       "       "    "         "          2-                                                                            pyr-                                                                          imidinyl-                                                                     methyl              265                                                                              "            "       "       "    "         "          4-pyr-                                                                        imidinyl-                                                                     methyl              266                                                                              "            "       "       3-OCH.sub.2                                                                        "         "          benzyl              267                                                                              CH.sub.2 CH.sub.2 CH.sub.2                                                                         "       H    "         "          3-thienyl-                                                                    methyl              268                                                                              "                    "       "    "         "          3-                                                                            pyridyl-                                                                      methyl              269                                                                              "                    "       "    "         "          2-furyl-                                                                      methyl              270                                                                              "                    "       "    "         "          3-furyl-                                                                      methyl              271                                                                              "                    "       "    (CH.sub.2).sub.2                                                                        "          4-amino-                                                                      benzyl              272                                                                              "                    "       "    "         "          2-amino-                                                                      benzyl              273                                                                              "                    "       "    "         "          4-acetyl-                                                                     amino-                                                                        benzyl              274                                                                              "                    "       "    "         "          3-acetyl-                                                                     amino-                                                                        benzyl              275                                                                              CH.sub.3     H       COH     "    CH.sub.2  "          benzyl              276                                                                              "            "       COC.sub.2 H.sub.5                                                                     "    "         "          "                   277                                                                              "            "       COC.sub.3 H.sub.7                                                                     "    "         "          "                   278                                                                              CH.sub.3     H       COC.sub.4 H.sub.9                                                                     H    CH.sub.2                                                                                 ##STR73## benzyl              279                                                                              "            "       COC.sub.6 H.sub.13                                                                    "    "         "          "                   280                                                                              "            "       COC.sub.8 H.sub.27                                                                    "    "         "          "                   281                                                                              "            "       COC.sub.10 H.sub.21                                                                   "    "         "          "                   282                                                                              "            "       H       "    "                                                                                        ##STR74## "                   283                                                                              "            "       "       "    "                                                                                        ##STR75## "                   284                                                                              "            "       "       "    "                                                                                        ##STR76## "                   285                                                                              "            "       "       3-Br "                                                                                        ##STR77## "                   286                                                                              "            "       "       3-C.sub.2 H.sub.5                                                                  "         "          "                   287                                                                              "            "       "       3-C.sub.3 H.sub.7                                                                  "         "          "                   288                                                                              "            "       "       3-OC.sub.2 H.sub.5                                                                 "         "          "                   289                                                                              "            "       "       3-OC.sub.3 H.sub.7                                                                 "         "          "                   290                                                                              "            "       "       3-OC.sub.4 H.sub.9                                                                 "         "          "                   291                                                                              "            "       "       H    "         "          4-ethoxy-                                                                     benzyl              292                                                                              "            "       "       "    "         "          4-butoxy-                                                                     benzyl              293                                                                              "            "       "       "    "         "          4-t-butyl-                                                                    benzyl              294                                                                              "            "       "       "    "         "          4-di-                                                                         fluoro-                                                                       methyl-                                                                       benzyl              295                                                                              CH.sub.3     H       H       H    CH.sub.2                                                                                 ##STR78## 4-(2- fluoro-                                                                 ethoxy)-                                                                      benzyl              296                                                                              "            "       "       "    "         "          4-                                                                            butyryl-                                                                      amino-                                                                        benzyl              297                                                                              H            OC.sub.3 H.sub.7                                                                      "       "    "         "          benzyl              298                                                                              "            OC.sub.4 H.sub.9                                                                      "       "    "         "          "                   299                                                                              CH.sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3)                                                            "       "    "         "          "                   300                                                                              CH.sub.2 CH.sub.2 CH(OCH.sub.2 CH.sub.2 C.sub.6 H.sub.5)                                           "       "    "         "          "                   301                                                                              CH.sub.3     H       "       "    "         "          phen-                                                                         ethyl               302                                                                              "            "       "       "    "         "          diphenyl-                                                                     methyl              303                                                                              C.sub.2 H.sub.5                                                                            "       "       3-OCH.sub.3                                                                        "         "          benzyl              304                                                                              "            "       "       3-F  "         "          "                   305                                                                              "            "       "       3-Cl "         "          "                   306                                                                              "            "       "       3-CH.sub.3                                                                         "         "          "                   307                                                                              "            "       "       H    "         "          2-thienyl-                                                                    methyl              308                                                                              C.sub.3 H.sub.7                                                                            "       "       3-OCH.sub.3                                                                        "         "          benzyl              309                                                                              "            "       "       3-F  "         "          "                   310                                                                              "            "       "       3-Cl "         "          "                   311                                                                              "            "       "       3-CH.sub.3                                                                         "         "          "                   312                                                                              "            "       "       H    "         "          2-thienyl-                                                                    methyl              313                                                                              i-C.sub.3 H.sub.7                                                                          H       H       3-OCH.sub.3                                                                        CH.sub.2                                                                                 ##STR79## benzyl              314                                                                              "            "       "       3-F  "         "          "                   315                                                                              "            "       "       3-Cl "         "          "                   316                                                                              "            "       "       3-CH.sub.3                                                                         "         "          "                   317                                                                              CH.sub.3     "       "       H    "         "          3-phenyl-                                                                     propyl              318                                                                              "            "       "       3-OCH.sub.3                                                                        "         "          2-thienyl-                                                                    methyl              319                                                                              "            "       "       3-F  "         "          2-thienyl-                                                                    methyl              320                                                                              "            "       "       3-Cl "         "          2-thienyl-                                                                    methyl              321                                                                              "            "       "       3-CH.sub.3                                                                         "         "          2-thienyl-                                                                    methyl              322                                                                              CH.sub.2 CH.sub.2 CH.sub.2                                                                 "       "       3-OCH.sub.3                                                                        "         "          2-thienyl-                                                                    methyl              323                                                                              "            "       "       3-F  "         "          2-thienyl-                                                                    methyl              324                                                                              "            "       "       3-Cl "         "          2-thienyl-                                                                    methyl              325                                                                              "            "       "       3-CH.sub.3                                                                         "         "          2-thienyl-                                                                    methyl              326                                                                              C.sub.2 H.sub.5                                                                            "       "       H    "         "          3-thienyl-                                                                    methyl              327                                                                              CH.sub.3     "       "       3-OCH.sub.3                                                                        "         "          3-thienyl-                                                                    methyl              328                                                                              "            "       "       3-F  "         "          3-thienyl-                                                                    methyl              329                                                                              "            "       "       3-Cl "         "          3-thienyl-                                                                    methyl              330                                                                              "            "       "       3-CH.sub.3                                                                         "         "          3-thienyl-                                                                    methyl              __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________    (Compound III)                                                                 ##STR80##                                                                        ##STR81##                                                                              ##STR82##                                                                               ##STR83##                                                                       ##STR84##                                                                            ##STR85##                                                                             ##STR86##                             __________________________________________________________________________     1 CH.sub.2 CH.sub.2 CH.sub.2                                                                       H double bond                                                                           ##STR87##                                                                            benzyl                                  2 "                  " single bond                                                                           ##STR88##                                                                            "                                       3 "                  " CH     "       "                                       4 "                  " CH.sub.2                                                                             "       "                                       5 "                  " CHCH.sub.2                                                                           "       "                                       6 "                  " (CH.sub.2).sub.2                                                                     "       "                                       7 "                  " double bond                                                                           ##STR89##                                                                            4-fluorobenzyl                          8 "                  " single bond                                                                           ##STR90##                                                                            "                                       9 "                  " CH     "       "                                       10                                                                              "                  " CH.sub.2                                                                             "       "                                       11                                                                              "                  " CHCH.sub.2                                                                           "       "                                       12                                                                              "                  " (CH.sub.2).sub.2                                                                     "       "                                       13                                                                              "                  " double bond                                                                           ##STR91##                                                                            3-fluorobenzyl                          14                                                                              "                  " single bond                                                                           ##STR92##                                                                            "                                       15                                                                              "                  " CH     "       "                                       16                                                                              "                  " CH.sub.2                                                                             "       "                                       17                                                                              "                  " CHCH.sub.2                                                                           "       "                                       18                                                                              "                  " (CH.sub.2).sub.2                                                                     "       "                                       19                                                                              CH.sub.2 CH.sub.2 CH.sub.2                                                                       H double bond                                                                           ##STR93##                                                                            2-fluorobenzyl                          20                                                                              "                  " single bond                                                                           ##STR94##                                                                            "                                       21                                                                              "                  " CH     "       "                                       22                                                                              "                  " CH.sub.2                                                                             "       "                                       23                                                                              "                  " CHCH.sub.2                                                                           "       "                                       24                                                                              "                  " (CH.sub.2).sub.2                                                                     "       "                                       25                                                                              "                  " double bond                                                                           ##STR95##                                                                            4-methoxybenzyl                         26                                                                              "                  " single bond                                                                           ##STR96##                                                                            "                                       27                                                                              "                  " CH.sub.2                                                                             "       "                                       28                                                                              "                  " CH.sub.2                                                                             "       "                                       29                                                                              "                  " CHCH.sub.2                                                                           "       "                                       30                                                                              "                  " (CH.sub.2).sub.2                                                                     "       "                                       31                                                                              "                  " double bond                                                                           ##STR97##                                                                            3-methoxybenzyl                         32                                                                              "                  " single bond                                                                           ##STR98##                                                                            "                                       33                                                                              "                  " CH     "       "                                       34                                                                              "                  " CH.sub.2                                                                             "       "                                       35                                                                              "                  " CHCH.sub.2                                                                           "       "                                       36                                                                              "                  " (CH.sub.2).sub.2                                                                     "       "                                       37                                                                              CH.sub.2 CH.sub.2 CH.sub.2                                                                       H double bond                                                                           ##STR99##                                                                            4-hydroxybenzyl                         38                                                                              "                  " single bond                                                                           ##STR100##                                                                           "                                       39                                                                              "                  " CH     "       "                                       40                                                                              "                  " CH.sub.2                                                                             "       "                                       41                                                                              "                  " CHCH.sub.2                                                                           "       "                                       42                                                                              "                  " (CH.sub.2).sub.2                                                                     "       "                                       43                                                                              "                  " double bond                                                                           ##STR101##                                                                           4-chlorobenzyl                          44                                                                              "                  " single bond                                                                           ##STR102##                                                                           "                                       45                                                                              "                  " CH     "       "                                       46                                                                              "                  " CH.sub.2                                                                             "       "                                       47                                                                              "                  " CHCH.sub.2                                                                           "       "                                       48                                                                              "                  " (CH.sub.2).sub.2                                                                     "       "                                       49                                                                              "                  " double bond                                                                           ##STR103##                                                                           3-chlorobenzyl                          50                                                                              "                  " single bond                                                                           ##STR104##                                                                           "                                       51                                                                              "                  " CH     "       "                                       52                                                                              "                  " CH.sub.2                                                                             "       "                                       53                                                                              "                  " CHCH.sub.2                                                                           "       "                                       54                                                                              "                  " (CH.sub.2).sub.2                                                                     "       "                                       55                                                                              CH.sub.2 CH.sub.2 CH.sub.2                                                                       H double bond                                                                           ##STR105##                                                                           2-chlorobenzyl                          56                                                                              "                  " single bond                                                                           ##STR106##                                                                           "                                       57                                                                              "                  " CH     "       "                                       58                                                                              "                  " CH.sub.2                                                                             "       "                                       59                                                                              "                  " CHCH.sub.2                                                                           "       "                                       60                                                                              "                  " (CH.sub.2).sub.2                                                                     "       "                                       61                                                                              "                  " double bond                                                                           ##STR107##                                                                           4-methylbenzyl                          62                                                                              "                  " single bond                                                                           ##STR108##                                                                           "                                       63                                                                              "                  " CH     "       "                                       64                                                                              "                  " CH.sub.2                                                                             "       "                                       65                                                                              "                  " CHCH.sub.2                                                                           "       "                                       66                                                                              "                  " (CH.sub.2).sub.2                                                                     "       "                                       67                                                                              "                  " double bond                                                                           ##STR109##                                                                           4-nitrobenzyl                           68                                                                              "                  " single bond                                                                           ##STR110##                                                                           "                                       69                                                                              "                  " CH     "       "                                       70                                                                              "                  " CH.sub.2                                                                             "       "                                       71                                                                              "                  " CHCH.sub.2                                                                           "       "                                       72                                                                              "                  " (CH.sub.2).sub.2                                                                     "       "                                       73                                                                              CH.sub.2 CH.sub.2 CH.sub.2                                                                       H double bond                                                                           ##STR111##                                                                           4-trifluoromethylbenzyl                 74                                                                              "                  " single bond                                                                           ##STR112##                                                                           "                                       75                                                                              "                  " CH     "       "                                       76                                                                              "                  " CH.sub.2                                                                             "       "                                       77                                                                              "                  " CHCH.sub.2                                                                           "       "                                       78                                                                              "                  " (CH.sub.2).sub.2                                                                     "       "                                       79                                                                              "                  " double bond                                                                           ##STR113##                                                                           sec-phenethyl                           80                                                                              "                  " single bond                                                                           ##STR114##                                                                           "                                       81                                                                              "                  " CH     "       "                                       82                                                                              "                  " CH.sub.2                                                                             "       "                                       83                                                                              "                  " CHCH.sub.2                                                                           "       "                                       84                                                                              "                  " (CH.sub.2).sub.2                                                                     "       "                                       85                                                                              "                  " double bond                                                                           ##STR115##                                                                           diphenylmethyl                          86                                                                              "                  " single bond                                                                           ##STR116##                                                                           "                                       87                                                                              "                  " CH     "       "                                       88                                                                              "                  " CH.sub.2                                                                             "       "                                       89                                                                              "                  " CHCH.sub.2                                                                           "       "                                       90                                                                              "                  " (CH.sub.2).sub.2                                                                     "       "                                       91                                                                              CH.sub.2 CH.sub.2 CH.sub.2                                                                       H double bond                                                                           ##STR117##                                                                           di(4-fluorophenyl)methyl                92                                                                              "                  " single bond                                                                           ##STR118##                                                                           "                                       93                                                                              "                  " CH     "       "                                       94                                                                              "                  " CH.sub.2                                                                             "       "                                       95                                                                              "                  " CHCH.sub.2                                                                           "       "                                       96                                                                              "                  " (CH.sub.2).sub.2                                                                     "       "                                       97                                                                              "                  " double bond                                                                           ##STR119##                                                                           2-thienylmethyl                         98                                                                              "                  " single bond                                                                           ##STR120##                                                                           "                                       99                                                                              "                  " CH     "       "                                      100                                                                              "                  " CH.sub.2                                                                             "       "                                      101                                                                              "                  " CHCH.sub.2                                                                           "       "                                      102                                                                              "                  " (CH.sub.2).sub.2                                                                     "       "                                      103                                                                              "                  " double bond                                                                           ##STR121##                                                                           2-pyridylmethyl                        104                                                                              "                  " single bond                                                                           ##STR122##                                                                           "                                      105                                                                              "                  " CH     "       "                                      106                                                                              "                  " CH.sub.2                                                                             "       "                                      107                                                                              "                  " CHCH.sub.2                                                                           "       "                                      108                                                                              "                  " (CH.sub.2).sub.2                                                                     "       "                                      109                                                                              CH.sub.2 CH.sub.2 CH.sub.2                                                                       H double bond                                                                           ##STR123##                                                                           4-pyridylmethyl                        110                                                                              "                  " single bond                                                                           ##STR124##                                                                           "                                      111                                                                              "                  " CH     "       "                                      112                                                                              "                  " CH.sub.2                                                                             "       "                                      113                                                                              "                  " CHCH.sub.2                                                                           "       "                                      114                                                                              "                  " (CH.sub.2).sub.2                                                                     "       "                                      115                                                                              "                  " double bond                                                                           ##STR125##                                                                           2-pyrimidinylmethyl                    116                                                                              "                  " single bond                                                                           ##STR126##                                                                           "                                      117                                                                              "                  " CH     "       "                                      118                                                                              "                  " CH.sub.2                                                                             "       "                                      119                                                                              "                  " CHCH.sub.2                                                                           "       "                                      120                                                                              "                  " (CH.sub.2).sub.2                                                                     "       "                                      121                                                                              "                  " double bond                                                                           ##STR127##                                                                           4-pyrimidinylmethyl                    122                                                                              "                  " single bond                                                                           ##STR128##                                                                           "                                      123                                                                              "                  " CH     "       "                                      124                                                                              "                  " CH.sub.2                                                                             "       "                                      125                                                                              "                  " CHCH.sub.2                                                                           "       "                                      126                                                                              "                  " (CH.sub.2).sub.2                                                                     "       "                                      127                                                                              H        H         H CH.sub.2                                                                              ##STR129##                                                                           benzyl                                 128                                                                              "        CH.sub.3  " "      "       "                                      129                                                                              "        C.sub.2 H.sub.5                                                                         " "      "       "                                      130                                                                              "        C.sub.3 H.sub.7                                                                         " "      "       "                                      131                                                                              "        i-C.sub.3 H.sub.7                                                                       " "      "       "                                      132                                                                              "        C.sub.4 H.sub.9                                                                         " "      "       "                                      133                                                                              "        sec-C.sub.4 H.sub.9                                                                     " "      "       "                                      134                                                                              "        C.sub.6 H.sub.13                                                                        " "      "       "                                      135                                                                              "        C.sub.8 H.sub.17                                                                        " "      "       "                                      136                                                                              "        C.sub.10 H.sub.21                                                                       " "      "       "                                      137                                                                              "        Cl        " "      "       "                                      138                                                                              "        Br        " "      "       "                                      139                                                                              "        OCH.sub.3 " "      "       "                                      140                                                                              "        OC.sub.2 H.sub.5                                                                        " "      "       "                                      141                                                                              CH.sub.3 CH.sub.3  " "      "       "                                      142                                                                              C.sub.2 H.sub.5                                                                        "         " "      "       "                                      143                                                                              C.sub.3 H.sub.7                                                                        "         " "      "       "                                      144                                                                              i-C.sub.3 H.sub.7                                                                      "         " "      "       "                                      145                                                                              C.sub.4 H.sub.9                                                                        CH.sub.3  H CH.sub.2                                                                              ##STR130##                                                                           benzyl                                 146                                                                              sec-C.sub.4 H.sub.9                                                                    "         " "      "       "                                      147                                                                              i-C.sub.4 H.sub.9                                                                      "         " "      "       "                                      148                                                                              C.sub.5 H.sub.11                                                                       "         " "      "       "                                      149                                                                              C.sub.7 H.sub.15                                                                       "         " "      "       "                                      150                                                                              C.sub.9 H.sub.19                                                                       "         " "      "       "                                      151                                                                              Cl       CH.sub.3  " "      "       "                                      152                                                                              Br       "         " "      "       "                                      153                                                                              CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                              " "      "       "                                      154                                                                              CH(CH.sub.3)CH.sub.2 CH.sub.2                                                                    " "      "       "                                      155                                                                              CH.sub.2 CH(CH.sub.3)CH.sub.2                                                                    " "      "       "                                      156                                                                              CH.sub.2 CH.sub.2 CH(CH.sub.3)                                                                   " "      "       "                                      157                                                                              CH.sub.2 CH.sub.2 CH(OH)                                                                         " "      "       "                                      158                                                                              CH.sub.2 CH.sub.2 CH(OCH.sub.3)                                                                  " "      "       "                                      159                                                                              CH.sub.2 CH.sub.2 CH(OC.sub.2 H.sub.5)                                                           " "      "       "                                      160                                                                              CH.sub.2 CH.sub.2 CH(OC.sub.3 H.sub.7)                                                           " "      "       "                                      161                                                                              CH.sub.2 CH.sub.2 CH(OCH.sub.2 CHCH.sub.2)                                                       " "      "       "                                      162                                                                              CH.sub.2 CH.sub.2 CH(OCH.sub.2 C.sub.6 H.sub.5)                                                  " "      "       "                                      163                                                                              CH.sub.2 CH.sub.2 CH(OCOH)                                                                       " "      "       "                                      164                                                                              CH.sub.2 CH.sub.2 CH(OCOCH.sub.3)                                                                H CH.sub.2                                                                              ##STR131##                                                                           benzyl                                 165                                                                              CH.sub.2 CH.sub.2 CH(OCOC.sub.2 H.sub.5)                                                         " "      "       "                                      166                                                                              CH.sub.2 CH.sub.2 CH(OCOC.sub.3 H.sub.7)                                                         " "      "       "                                      167                                                                              CH.sub.2 CH.sub.2 CH(OCOC.sub.5 H.sub.11)                                                        " "      "       "                                      168                                                                              CH.sub.2 CH.sub.2 CH(OCOC.sub.9 H.sub.19)                                                        " "      "       "                                      169                                                                              CH.sub.2 CH.sub.2 CH(OCOCH.sub.2 C.sub.6 H.sub.5)                                                " "      "       "                                      170                                                                              CH.sub.2 CH.sub.2 CH(OCOC.sub.6 H.sub.5)                                                         " "      "       "                                      171                                                                              CH.sub.2 CH.sub.2 CH(F)                                                                          " "      "       "                                      172                                                                              CH.sub.2 CH.sub.2 CH(Cl)                                                                         " "      "       "                                      173                                                                              CH.sub.2 CH.sub.2 CH(Br)                                                                         " "      "       "                                      174                                                                              CH.sub.2 CH.sub.2 C(F).sub.2                                                                     " "      "       "                                      175                                                                              CH(Br)CH.sub.2 CH(Br)                                                                            " "      "       "                                      176                                                                              CH.sub.3 Cl        " "      "       "                                      177                                                                              "        Br        " "      "       "                                      178                                                                              "        CH.sub.2 OH                                                                             " "      "       "                                      179                                                                              "        CH.sub.2 OCH.sub.3                                                                      " "      "       "                                      180                                                                              "        CH.sub.2 OCOCH.sub.3                                                                    " "      "       "                                      181                                                                              "        CH.sub.2 F                                                                              " "      "       "                                      182                                                                              "        CH.sub.2 Cl                                                                             " "      "       "                                      183                                                                              CH.sub.2 CH.sub.2 CH.sub.2                                                                       H CH.sub.2                                                                              ##STR132##                                                                           2-pyrimidinylmethyl                    184                                                                              CH.sub.2 C(CH.sub.3).sub.2 CH.sub.2                                                              " "      "       benzyl                                 185                                                                              CH.sub.2 CH.sub.2 CH(OC.sub.6 H.sub.5)                                                           " "      "       "                                      __________________________________________________________________________

In the formula (II), the compounds (IIa to e) wherein R⁴ is a hydrogenatom can be prepared by [Preparation process 1-1], [Preparation process2-1], [Preparation process 3-1] or [Preparation process 4-1], and in theformula (III), the compounds (IIIa to e) wherein R⁴ is a hydrogen atomcan be prepared by [Preparation process 1-2], [Preparation process 2-2],[Preparation process 3-2] or [Preparation process 4-2].

On the other hand, in the formula (II), the compound (IIf) wherein R⁴ isan acyl group can be prepared by [Preparation process 5-1] and in theformula (III), the compound (IIIf) wherein R⁴ is an acyl group can beprepared by [Preparation process 5-2]. ##STR133##

(wherein R¹, R², R³, R⁵, R⁶, X, Y and . . . have the same meanings asdescribed above and Z represents a halogen atom)

In [Preparation process 1-1] or [Preparation process 1-2], the compound(IIa) or (IIIa) is prepared by reacting the compound (IV) or (VI) withthe compound (V) in a 1- to 5-fold molar amount, preferably a 1- to2-fold molar amount in a solvent in the presence or absence of an acid.

The solvent to be used is not particularly limited so long as it isinert to the above reactions, and may include, for example, alcoholssuch as methanol, ethanol, propanol, isopropanol, butanol, etc.; aproticpolar solvents such as dimethylformamide, dimethyl sulfoxide,dimethylacetamide, hexamethylphosphoric acid triamide, etc.; halogenatedhydrocarbons such as chloroform, carbon tetrachloride, dichloroethane,etc.; esters such as ethyl acetate, etc.; and nitriles such asacetonitrile, etc. Preferred are the aforesaid alcohols, halogenatedhydrocarbons and aprotic polar solvents.

As the acid to be used, there may be mentioned, for example, a Brφnstedacid such as hydrochloric acid, sulfuric acid, phosphoric acid, aceticacid, propionic acid, methanesulfonic acid, benzenesulfonic acid,p-toluene-sulfonic acid, etc.; and a Lewis acid such as stannouschloride, stannic chloride, zinc chloride, aluminum chloride, titaniumtetrachloride, etc., preferably hydrochloric acid, stannous chloride,stannic chloride and zinc chloride. The amount to be used is generally a0.01- to 10-fold molar amount, preferably a 0.1- to 5-fold molar amountbased on the compound (V).

The reaction temperature is 0° to 200° C., preferably the reaction iscarried out in the range of 0° to 150° C. The reaction time variesdepending on conditions other than those described above, but thereaction is carried out generally for 5 minutes to 24 hours, preferablyfor 10 minutes to 12 hours.

The compound (IV) is generally used as a free material, but a salt withthe Brφnsted acid or a complex with the Lewis acid as mentioned abovemay be also used. In that case, the reaction can proceed smoothlywithout further adding the Brφnsted acid or Lewis acid as mentionedabove to the reaction system.

Also, when the compound (IV) or (VI) wherein R⁵ is a hydroxy group isreacted in the aforesaid alcohol in the presence of an acid, as theformed compound (IIa) or (IIIa), in addition to the compound wherein R⁵is a hydroxy group, a compound (for example, in the reaction in ethanol,a compound wherein R₅ is an ethoxy group) wherein R⁵ is an alkoxy groupwhich can be obtained by replacing the hydroxy group with an alcohol ofthe solvent and a compound having a double bond which is a dehydratedproduct can be obtained. ##STR134##

(wherein R¹, R², R³, R⁶ and p have the same meanings as described above)

In [Preparation process 2-1] or [Preparation process 2-2], the compound(IIb), (IIc), (IIIb) or (IIIc) is prepared by subjecting the compound(VII) or (X) and the compound (VIII) or (IX) in a 1- to 5-fold molaramount, preferably a 1- to 2-fold molar amount to condensation reactionin a solvent in the presence of a base.

The solvent to be used is not particularly limited so long as it isinert to the above reactions, and may include, for example, alcoholssuch as methanol, ethanol, propanol, isopropanol, butanol, etc.; etherssuch as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,etc.; aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, dimethylacetamide, etc.; nitriles such as acetonitrile, etc.;and esters such as ethyl acetate, etc. Preferred are the above alcohols,ethers and nitriles.

As the base to be used, there may be mentioned, for example, alkalimetal alkoxides such as sodium methoxide, sodium ethoxide, potassiumt-butoxide, etc.; alkyl lithiums such as butyl lithium, t-butyl lithium,etc.; alkali metal hydrides such as sodium hydride, lithium hydride,etc.; alkali metal amides such as sodium amide, etc.; amines such astriethylamine, tributylamine, diisopropylethylamine, pyridine, picoline,luridine, etc.; alkali metal hydroxides such as sodium hydroxide,potassium hydroxide, etc.; and alkali metal carbonates such as sodiumcarbonate, potassium carbonate, etc. Preferred are the above alkalimetal alkoxides, alkyl lithiums, alkali metal hydrides and amines. Theamount to be used is generally a 1- to 10-fold molar amount, preferablya 1- to 5-fold molar amount based on the compound (VII) or (X).

The reaction temperature is -70° to 150° C., preferably the reaction iscarried out in the range of -50° to 100° C. The reaction time variesdepending on conditions other than those described above, but thereaction is carried out generally for 15 minutes to 100 hours,preferably for 30 minutes to 72 hours. ##STR135##

(wherein R¹, R², R³, R⁶ and p have the same meanings as described above)

In [Preparation process 3-1] or [Preparation process 3-2], the compound(IId), (IIe), (IIId) or (IIIe) is prepared by subjecting the compound(IIb), (IIc), (IIIb) or (IIIc) to catalytic reduction with a hydrogengas in a solvent in the presence of a catalyst or to reduction by areducing agent.

The solvent to be used when catalytic reduction with a hydrogen gas iscarried out is not particularly limited so long as it is inert to theabove reaction, and may include, for example, alcohols such as methanol,ethanol, propanol, isopropanol, butanol, etc.; ethers such as diethylether, tetrahydrofuran, dioxane, etc.; water; and acetic acid. Preferredare the above alcohols. When the compound (IIb), (IIc), (IIIb) or (IIIc)is not easily dissolved in the above solvent, dissolution can beaccelerated by a method of mixing these solvents, adding a small amountof hydrochloric acid, etc., whereby the reaction can be accelerated.

As the catalyst to be used, there may be mentioned, for example, a noblemetal type catalyst such as platinum oxide, palladium-carbon,platinum-carbon, etc., preferably platinum oxide and palladium-carbon.The amount of the catalyst to be used is generally 0.01 to 50% byweight, preferably 0.1 to 50% by weight based on the compound (IIb),(IIc), (IIIb) or (IIIc).

The hydrogen gas may be passed to the reaction mixture at normalpressure or may be reacted in an autoclave under pressurization up to100 kg/cm². The pressure is preferably normal pressure to 50 kg/cm².

The reaction temperature is 0° to 200° C., preferably the reaction iscarried out in the range of 0° to 150° C. The reaction time variesdepending on conditions other than those described above, but thereaction is carried out generally for 10 minutes to 24 hours, preferablyfor 15 minutes to 12 hours.

On the other hand, when reduction is carried out by using a reducingagent, as the reducing agent, preferred is a reducing agent used forreduction of an αβ-unsaturated ketone, such as metallic lithium-ammonia,triethylsilane-trifluoroacetic acid, triphenyltin hydride, lithiumaluminum hydride-cuprous iodide, etc. These reactions can be carriedout, for example, under conditions described in "New ExperimentalChemistry Lecture" edited by the Japan Chemical Society, vol. 14 (I), p.5. ##STR136##

(wherein R¹, R², R³, R⁵, R⁶ X, Y, Z and . . . have the same meanings asdescribed above and R⁷ represents a protective group such as at-butoxycarbonyl group, a benzyloxycarbonyl group, an acetyl group, atrifluoroacetyl group, a benzoyl group, a triphenylmethyl group and amethoxymethyl group)

In [Preparation process 4-1] or [Preparation process 4-2], the compound(IIa) or (IIIa) can be also prepared by reacting the compound (IV') or(VI') having the protective group R⁷ with the compound (V) to preparethe compound (II'a) or (III'a), removing the protective group and thencarrying out alkylation.

The protective group R⁷ may be any protective group generally used as aprotective group for an amino group, and there may be mentioned, forexample, a protective group such as a t-butoxycarbonyl group, abenzyloxycarbonyl group, an acetyl group, a trifluoroacetyl group, abenzoyl group, a triphenylmethyl group and a methoxymethyl group.

The reactions for obtaining the compound (II'a) from the compounds (IV')and (V) and the compound (III'a) from the compounds (VI') and (V) can becarried out according to the same method as described above in[Preparation process 1-1] and [Preparation process 1-2].

The deprotection reaction for obtaining the compound (XI) from thecompound (II'a) or the compound (XIII) from the compound (III'a) can becarried out by suitably selecting from methods described in literature(e.g. T. W. Greene, "Protective Groups in Organic Synthesis" John Wiley& Sons), for example, a method using an acid, an alkali or hydrogenreduction, etc.

In the alkylation reactions for obtaining the compound (IIa) from thecompound (XI) and the compound (IIIa) from the compound (XIII), thesolvent to be used is not particularly limited so long as it is inert tothe above reactions, and may include, for example, ketones such asacetone, methyl ethyl ketone, etc.; ethers such as diethyl ether,tetrahydrofuran, dioxane, etc.; alcohols such as methanol, ethanol,propanol, isopropanol, butanol, etc.; aprotic polar solvents such asdimethylformamide, dimethyl sulfoxide, dimethylacetamide,hexamethylphosphoric acid triamide, etc.; halogenated hydrocarbons suchas chloroform, dichloromethane, dichloroethane, etc. and others.

It is generally desired to carry out the above reactions in the presenceof a base. As the base, there may be mentioned alkali metal carbonatessuch as sodium carbonate, potassium carbonate, etc.; and amines such astriethylamine, tributylamine, diisopropylethylamine, pyridine, picoline,etc.

The reaction temperature is 0° to 150° C., preferably the reaction iscarried out in the range of 0° to 100° C. The reaction time is generally15 minutes to 72 hours, preferably the reaction is carried out for 30minutes to 24 hours. ##STR137##

(wherein R¹, R², R³, R⁵, R⁶, X, Y, Z and . . . have the same meanings asdescribed above and R^(4') represents the same acyl group described inR⁴)

In [Preparation process 5-1] or [Preparation process 5-2], the compound(IIf) or (IIIf) is prepared by reacting the compound (IIa) or (IIIa)with the acyl halide (XIV) in a 1- to 5-fold molar amount, preferably a1- to 2-fold molar amount in the presence of a base.

The solvent to be used is not particularly limited so long as it isinert to the above reactions, and may include, for example, halogenatedhydrocarbons such as methylene chloride, chloroform, dichloroethane,etc.; aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, dimethylacetamide, hexamethylphosphoric acid triamide, etc.;esters such as ethyl acetate, etc.; and nitriles such as acetonitrile,etc. Preferred are halogenated hydrocarbons and aprotic polar solvents.

As the base to be used, there may be mentioned amines such astriethylamine, tributylamine, diisopropylethylamine, pyridine, picoline,lutidine, etc.; alkali metal carbonates such as sodium carbonate,potassium carbonate, etc. and others. Preferred are amines. The amountto be used is generally a 1- to 10-fold molar amount, preferably a 1- to5-fold molar amount based on the acyl halide.

The reaction temperature is -70° to 150° C., preferably the reaction iscarried out in the range of -50° to 100° C. The reaction time variesdepending on conditions, but the reaction is carried out generally for15 minutes to 100 hours, preferably for 30 minutes to 72 hours.

In the compound (II) or (III), when at least one of R¹, R² and R³ has afunctional group such as a hydroxy group, an amino group, etc., thesecan be converted into an acyloxy group, an acylamino group, etc.,respectively, according to a known method, for example, by subjecting itto acylation reaction. When it has a nitro group, it can be convertedinto an amino group by reduction reaction.

The compounds (VIII) and (IX) to be used in the above [Preparationprocess 2-1] and [Preparation process 2-2] are known compounds orcompounds easily prepared from known compounds according to aconventional method.

The compounds (V), (VII) and (X) to be used as starting materials in[Preparation process 1-1], [Preparation process 1-2], [Preparationprocess 2-1], [Preparation process 2-2], [Preparation process 4-1] and[Preparation process 4-2] can be prepared easily according to knownmethods (see Japanese Provisional Patent Publication No. 203072/1982 andJapanese Provisional Patent Publication No. 70/1987). The compounds(IV), (VI), (IV') and (VI') to be used as starting materials in[Preparation process 1-1], [Preparation process 1-2], [Preparationprocess 4-1] and [Preparation process 4-2] can be prepared by[Preparation process 6-1], [Preparation process 6-2], [Preparationprocess 8-1], [Preparation process 8-2], [Preparation process 9-1] and[Preparation process 9-2] shown below. ##STR138##

(wherein R³, R⁶ and p have the same meanings as described above and R⁸represents a methyl group, an ethyl group or a phenyl group) ##STR139##

(wherein R³ and p have the same meanings as described above)

The condensation reactions of [Preparation process 6-1] and [Preparationprocess 6-2] are carried out by the same methods as described above in[Preparation process 2-1] and [Preparation process 2-2], or carried outby a known method known as the Horner-Wadsworth-Emmons reaction (see,for example, M. A. Blanchette et at., Tetrahedron Letters, vol. 25,2183).

In the reduction reactions of [Preparation process 6-1] and [Preparationprocess 6-2], partial reduction reactions for obtaining the compound(IVa) from the compound (XVIa), the compound (IVc) from the compound(XVIb), the compound (VIa) from the compound (XVIIIa) and the compound(VIc) from the compound (XVIIIb) are carried out by a method of usingstannous chloride, tin, zinc or iron, preferably stannous chloride ortin under acidic conditions or using zinc under neutral or alkalineconditions. As the solvent to be used for these reactions, there may bementioned, in addition to alcohols such as methanol, ethanol, propanol,etc., acetonitrile, acetic acid, water, etc. Preferred are alcohols,acetic acid and water. These may be used as a mixture. Further, as theacid to be used, there may be mentioned mineral acids such ashydrochloric acid, sulfuric acid and phosphoric acid or organic acidssuch as acetic acid and propionic acid. Preferred are hydrochloric acid,sulfuric acid and acetic acid. As the alkali, there may be mentioned analkali metal hydroxide such as sodium hydroxide and potassium hydroxide.The reactions are carried out generally at a temperature of 0° to 200°C., preferably in the range of 0° to 150° C. for 30 minutes to 72 hours,preferably 1 hour to 24 hours.

On the other hand, in the reduction reactions of [Preparation process6-1] and [Preparation process 6-2], simultaneous reduction reactions ofnitro groups and double bonds for obtaining the compound (Ivb) from thecompound (XVIa), the compound (IVd) from the compound (XVIb), thecompound (VIb) from the compound (XVIIIa) and the compound (VId) fromthe compound (XVIIIb) are carried out by the same methods as describedabove in [Preparation process 3-1] and [Preparation process 3-2].

The nitro compounds (XVIa), (XVIb), (XVIIIa) and (XVIIIb) which areintermediates in [Preparation process 6-1] and [Preparation process 6-2]and the compounds (IV') (i.e., IV'a, IV'b, IV'c and IV'd) and thecompounds (VI') (i.e., VI'a, VI'b, VI'c and VI'd) which are startingmaterials in [Preparation process 4-1] and [Preparation process 4-2] canbe also prepared by [Preparation process 7-1] and [Preparation process7-2] shown below. ##STR140##

(wherein R³, R⁶, R⁷, Z and p have the same meanings as described above)##STR141##

(wherein R³, R⁷ and p have the same meanings as described above)

The condensation reactions of [Preparation process 7-1] and [Preparationprocess 7-2] are carried out by the same methods as described above in[Preparation process 6-1] and [Preparation process 6-2], and thedeprotection reactions are carried out in the same manner as in[Preparation process 4-1] and [Preparation process 4-2], by suitablyselecting a known method of using an acid, an alkali or hydrogenreduction, etc. Also, the N-alkylation reaction by the compound (XII) iscarried out by the same methods as described above in [Preparationprocess 4-1] and [Preparation process 4-2], and the reduction reactionsof the compounds (XVI'a), (XVI'b), (XVIII'a) and (XVIII'b) can becarried out by the same methods as described above in [Preparationprocess 6-1] and [Preparation process 6-2]. ##STR142##

(wherein R³, R⁶ and p have the same meanings as described above and R⁹represents a protective group such as a t-butoxycarbonyl group, abenzyloxycarbonyl group, an acetyl group, a trifluoroacetyl group and abenzoyl group) ##STR143##

(wherein R³, R⁹ and p have the same meanings as described above)

In [Preparation process 8-1] or [Preparation process 8-2], the compound(XXIIa), (XXIId), (XXIVa) or (XXIVd) is prepared by subjecting thecompound (XXI) or (XXIII) with the compound (VIII) or (IX) in a 1- to5-fold molar amount, preferably a 1- to 2-fold molar amount tocondensation reaction in a solvent in the presence of a strong base.

R⁹ as the protective group is not particularly limited so long as it isstable under these reaction conditions, and preferred are at-butoxycarbonyl group, a benzyloxycarbonyl group, an acetyl group, atrifluoroacetyl group, a benzoyl group, etc.

As the solvent to be used, there may be mentioned ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, etc.; aliphatic andaromatic hydrocarbons such as pentane, hexane, cyclohexane, benzene,toluene, etc.; and aprotic polar solvents such as hexamethylphosphoricacid triamide, dimethyl sulfoxide, etc. Also, a mixture of thesesolvents may be used.

As the strong base to be used, preferred are alkyl lithiums such asn-butyl lithium, t-butyl lithium, etc.; alkali metal amides such aslithium diisopropylamide, lithium ditrimethylsilylamide, sodium amide,etc.; and alkali metal hydrides such as sodium hydride, potassiumhydride, etc. The amount to be used is generally a 1- to 5-fold molaramount, preferably a 2- to 3-fold molar amount based on the compound(XXI) or (XXIII).

The reaction temperature is -70° to 100° C., preferably the reaction iscarried out in the range of -70° to 50° C.

The dehydration reactions of [Preparation process 8-1] and [Preparationprocess 8-2] are generally carried out by suitably selecting fromvarious known methods used when an olefin is synthesized from analcohol. There may be mentioned, for example, a dehydration method underacidic conditions using an inorganic acid such as hydrochloric acid,sulfuric acid, phosphoric acid, etc.; or an organic acid such asp-tolunesulfonic acid, benzenesulfonic acid, etc., or a dehydrationmethod in the coexistence of a dehydrating agent such as thionylchloride, phosphorus oxychloride, methanesulfonic acid chloride,methanesulfonic anhydride, acetic anhydride, etc. and an organic basesuch as pyridine, picoline, lutidine,1,8-diazabicyclo[5.4.0.]-7-undecene, triethylamine, etc. Particularlywhen the protective group R⁹ is unstable under acidic conditions, thelatter method is preferred.

In the above dehydration reactions, as in the examples of the compounds(XXIIe) and (XXIIf), and (XXIVe) and (XXIVf), isomers having the doublebond at different positions may be produced. These may be separated andused or may be used as a mixture when they are used for the reductionreactions.

The reduction reactions of [Preparation process 8-1] and [Preparationprocess 8-2] are carried out by the same methods as described above in[Preparation process 3-1] and [Preparation process 3-2].

By deprotecting the above compounds (XXIIa), (XXIIb), (XXIIc), (XXIId),(XXIIe), (XXIIf), (XXIIg), (XXIVa), (XXIVb), (XXIVc), (XXIVd), (XXIVe),(XXIVf) and (XXIVg), the compounds (IVe), (IVa), (IVb), (IVf), (IVc),(IVg), (IVd), (VIe), (VIa), (VIb), (VIf), (VIc), (VIg) and (VId) areprepared, respectively. The deprotection reactions are carried out bythe same methods as described above in [Preparation process 4-1] and[Preparation process 4-2]. ##STR144##

(wherein R³, R⁶, R⁷, R⁹, Z and p have the same meanings as describedabove) ##STR145##

(wherein R³, R⁶, R⁷, R⁹, Z and p have the same meanings as describedabove)

In [Preparation process 9-1] and [Preparation process 9-2], thecondensation reactions, dehydration reactions and reduction reactionsare carried out by the same methods as described in [Preparation process8-1] and [Preparation process 8-2].

R⁷ and R⁹ as protective groups may be different or may be the same. Therespective compounds obtained in the respective reactions of[Preparation process 9-1] and [Preparation process 9-2] are supplied tothe deprotection reactions, respectively. In this case, by suitablyselecting the kinds of the two protective groups R⁷ and R⁹ or suitablyselecting deprotection conditions, either one of R⁷ and R⁹ can beselectively removed. Also, both of them can be removed simultaneously.The selections of these R⁷ and R⁹ and deprotection conditions can becarried out by referring to literature, for example, T. W. Greene,"Protective Groups in Organic Synthesis" John Wiley & Sons.

The compounds (XXVa), (XXVIa), (XXVb), (XXVIb), (XXVc), (XXVIc), (XXVd),(XXVId), (XXVe), (XXVIe), (XXVf), (XXVIf), (XXVg), (XXVIg), (XXVIIa),(XXVIIIa), (XXVIIb), (XXVIIIb), (XXVIIc), (XXVIIIc), (XXVIId),(XXVIIId), (XXVIIe), (XXVIIIe), (XXVIIf), (XXVIIIf), (XXVIIg) and(XXVIIIg) thus obtained can be converted into (XXIIa), (IVe), (XXIIb),(IVa), (XXIIc), (IVb), (XXIId), (IVf), (XXIIe), (IVc), (XXIIf), (IVg),(XXIIg), (IVd), (XXIVa), (VIe), (XXIVb), (VIa), (XXIVc), (VIb), (XXIVd),(VIf), (XXIVe), (VIc), (XXIVf), (VIg), (XXIVg) and (VId), respectively,by subjecting to alkylation using the compound (XII) (R³ -Z) by the samemethods as described above in [Preparation process 4-1] and [Preparationprocess 4-2], respectively.

After completion of the reactions, the desired compounds of therespective reactions can be obtained by treating the reaction mixturesaccording to a conventional method and further can be purified by usinga conventional purification means such as recrystallization, columnchromatography, etc., if necessary. The compounds of the formula (I),the formula (II) and the formula (III) of the present invention areconverted into desired salts according to a conventional method, ifnecessary.

In the compounds of the formula (I), the formula (II) and the formula(III) thus prepared, optical isomers or geometric (cis and trans or Eand Z) isomers may exist. In that case, by carrying out the abovereactions by using starting compounds which are optically resolved orseparated as desired, optical isomers or geometric isomers of thecorresponding desired compounds can be obtained. Also, by treating amixture of optical isomers or geometric isomers according to aconventional optical resolution method or separation method, therespective isomers can be obtained.

In the formula (I), the formula (II) and the formula (III), all ofoptical isomers, geometric isomers and mixtures thereof are representedby the same formulae, but the respective isomers and mixtures thereofare included in the present invention as a matter of course.

BEST MODE FOR PRACTICING THE INVENTION

In the following, the present invention is described in detail byshowing Examples, but the scope of the present invention is not limitedby these.

EXAMPLE 1(E)-N-(5,6-dimethylpyrimidin-4-yl)-4-[3-(1-benzyl-piperidin-4-yl)propenoyl]aniline(Compound II-199 in Table 1)

1.27 g of 4-[3-(1-benzylpiperidin-4-yl)propenoyl]-nitrobenzene was addedto a mixed solution of 10 ml of acetic acid and 2 ml of hydrochloricacid, and then 1.38 g of stannous chloride was added thereto under icecooling. The mixture was stirred for 24 hours while further adding 0.69g of stannous chloride twice during the reaction. The solvent wasremoved under reduced pressure to obtain a crude product of(E)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]aniline. Then, this wasdissolved in 15 ml of ethanol, and to the solution was added 0.67 g of4-chloro-5,6-dimethylpyrimidine. Subsequently, the mixture was reactedby heating at 60° C. for 30 minutes. The reaction mixture wasneutralized by adding a 28% sodium methylate-methanol solution undercooling, solids were removed by filtration, and then the filtrate wasconsensed under reduced pressure. The obtained residue was applied tosilica gel column chromatography to obtain 1.02 g of the title compoundas pale yellow powder.

m.p. 188° to 190° C. (decomposed)

Mass; m/z=426 (M⁺)

NMR (δ, CDCl₃); 1.45 to 1.87 (4H, m), 1.96 to 2.13 (2H, m), 2.13 to 2.40(1H, m), 2.22 (3H, s), 2.49 (3H, s), 2.86 to 3.02 (2H, m), 3.52 (2H, s),6.62 (1H, s, br), 6.87 (1H, d, J=15.6 Hz), 7.03 (1H, dd, J=15.6 Hz,J=6.5 Hz), 7.18 to 7.43 (5H, m), 7.74 (2H, d, J=8.8 Hz), 7.96 (2H, d,J=8.8 Hz), 8.58 (1H, s)

EXAMPLE 2N-(5,6-dimethylpyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline(Compound II-150 in Table 1)

0.82 g of(E)-N-(5,6-dimethylpyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]anilineobtained in Example 1 was added to a mixed solvent of 30 ml of ethanoland 40 ml of dioxane, and then 0.05 g of platinum oxide was addedthereto. The mixture was stirred in a hydrogen stream at roomtemperature for 3.5 hours. After the catalyst was removed by filtration,the filtrate was condensed under reduced pressure. The obtained residuewas applied to silica gel column chromatography to obtain 0.39 g of thetitle compound as pale yellow powder.

m.p. 168° to 170° C.

Mass; m/z =428 (M⁺)

NMR (δ, CDCl₃); 1.20 to 1.46 (3H, m), 1.60 to 1.85 (4H, m), 1.85 to 2.07(2H, m), 2.22 (3H, s), 2.49 (3H, s), 2.83 to 3.04 (4H, m), 3.50 (2H, s),6.60 (1H, s, br), 7.20 to 7.40 (5H, m), 7.72 (2H, d, J=8.8 Hz), 7.96(2H, d, J=8.8 Hz), 8.58 (1H, s)

EXAMPLE 3N-(5-chloro-6-methylpyrimidin-4-yl)-4-[3-(1-benzyl-piperidin-4-yl)propanoyl]aniline·2HCl(2HCl salt of Compound II-160 in Table 1)

0.29 g of N- (5-chloro-6-methylpyrimidin-4-yl) -4- [3-(1-benzylpiperidin-4-yl)propanoyl]aniline obtained in the same manner asin Example 1 was dissolved in a mixed solvent of 10 ml of ethyl acetateand 5 ml of ethanol, and a hydrogen chloride gas-saturated ethyl acetatesolution was added to the mixture until the pH became 3. Crystalsprecipitated were collected by filtration and dried to obtain 0.21 g ofthe title compound as white powder.

(as 1/2H₂ O adduct)

m.p. 217° to 220° C.

Mass; m/z=448 (M⁺)

NMR (δ, CDCl₃ -DMSO-d₆); 1.70 to 1.90 (7H, m), 2.71 (3H, s), 2.82 to3.23 (4H, m), 3.34 to 3.42 (2H, m), 4.28 (2H, d, J=4.9 Hz), 7.43 to 7.46(3H, m), 7.67 to 7.69 (2H, m), 7.83 (2H, d, J=8.8 Hz), 8.00 (2H, d,J=8.8 Hz), 8.71 (1H, s), 10.24 (1H, s), 11.15 (1H, s, br)

In the same manner as in Example 1, Example 2 or Example 3, thefollowing compounds were synthesized.

EXAMPLE 4 (E) -N- (5-chloro-6-methylpyrimidin-4-yl )-4-[3-(1-benzylpiperidin-4-yl)propenoyl]aniline (Compound II-162 inTable 1)

White powder

m.p. 164° to 166° C.

Mass; m/z=446 (M⁺)

NMR (δ, CDCl₃); 1.49 to 1.70 (2H, m), 1.73 to 1.88 (2H, m), 1.98 to 2.10(2H, m), 2.18 to 2.36 (1H, m), 2.59 (3H, s), 2.90 to 2.98 (2H, m), 3.52(2H, s), 6.87 (1H, d, J=15 to 16 Hz), 7.04 (1H, dd, J=15 to 16 Hz, J=6to 7 Hz), 7.41 (1H, s), 7.79 (2H, d, J=8 to 9 Hz), 7.98 (2H, d, J=8 toHz), 8.58 (1H, s)

EXAMPLE 5N-(6-chloropyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline.multidot.HCl(HCl salt of Compound II-146 in Table 1)

(as 1/2H₂ O adduct)

Pale yellow powder

m.p. 246° to 260° C. (decomposed)

Mass; m/z=434 (M⁺)

NMR (δ, CDCl₃ -DMSO-d₆); 1.40 to 1.72 (4H, m), 1.72 to 2.03 (3H, m),2.77 to 3.20 (6H, m), 4.22 (2H, d, J=4.9 Hz), 6.95 (1H, s), 7.38 to 7.49(3H, m), 7.38 to 7.63 (2H, m), 7.83 (2H, d, J=8.8 Hz ), 7.93 (2H, d,J=8.8 Hz ), 8.52 (1H, s ), 10.05 (1H, br), 10.28 (1H, s)

EXAMPLE 6(E)-N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]aniline(Compound II-5 in Table 1)

Pale yellow powder

m.p. 212° to 214° C.

Mass; m/z=438 (M⁺)

NMR (δ, CDCl₃); 1.46 to 1.87 (4H, m), 1.93 to 2.38 (5H, m), 2.78 to 3.06(6H, m), 3.52 (2H, s), 6.61 (1H, s, br), 6.87 (1H, d, J=15.6 Hz), 7.04(1H, dd, J=15.6 Hz, J=6.4 Hz), 7.20 to 7.40 (5H, m), 7.77 (2H, d, J=8.8Hz), 7.96 (2H, d, J=8.8 Hz ), 8.65 (1H, s )

EXAMPLE 7N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3(1-benzylpiperidin-4-yl)propanoyl]aniline(Compound II-2 in Table 1)

Pale yellow powder

m.p. 203° to 205° C.

Mass; m/z=440 (M⁺)

NMR (δ, CDCl₃); 1.23 to 1.41 (3H, m), 1.63 to 1.77 (4H, m), 1.88 to 1.99(2H, m), 2.14 to 2.26 (2H, m), 2.78 to 3.07 (8H, m), 3.49 (2H, s), 6.49(1H, s), 7.20 to 7.30 (2H, m), 7.20 to 7.26 (3H, m), 7.76 (2H, d, J=8.8Hz), 9.96 (2H, d, J=8.8 Hz ), 8.65 (1H, s )

EXAMPLE 8N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3(1-benzylpiperidin-4-yl)propanoyl]aniline.2HCl (2HCl salt of Compound II-2 in Table 1)

(as H₂ O adduct)

Grayish white crystal

m.p. 198° to 201° C. (decomposed)

Mass; m/z=440 (M⁺)

NMR (δ, CDCl₃ -DMSO-d₆); 1.52 to 2.21 (7H, m), 2.20 to 2.42 (2H, m),2.68 to 3.55 (10H, m), 4.21 (2H, d, J=4.9 Hz), 7.38 to 7.52 (3H, m),7.60 to 7.80 (2H, m), 7.80 to 8.03 (4H, m), 8.60 (1H, s), 11.53 to 11.80(1H, m, br)

EXAMPLE 9(E)-N-(5,6,7,8-tetrahydroquinazolin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]aniline(Compound II-175 in Table 1)

White crystal

m.p. 171° to 172° C.

Mass (CI); m/z=453 (M⁺ +1)

NMR (δ, CDCl₃); 1.52 to 2.15 (10H, m), 2.18 to 2.36 (1H, m), 2.56 to2.60 (2H, m), 2.82 to 2.88 (2H, m), 2.92 to 3.13 (2H, m), 3.55 (2H, s),6.56 (1H, s), 6.87 (1H, d, J=15.6 Hz), 7.04 (1H, dd, J=6.4 Hz, J=15.6Hz), 7.25 to 7.35 (5H, m), 7.77 (2H, d, J=8.8 Hz), 7.97 (2H, d, J=8.8Hz), 8.60 (1H, s)

EXAMPLE 10N-(5,6,7,8-tetrahydroquinazolin-4-yl)-4-[3-(1-benzyl-piperidin-4-yl)propanoyl]aniline(Compound II-163 in Table 1)

(as 3/4H₂ O adduct)

White crystal

m.p. 156° to 157° C.

Mass (CI); m/e=455 (M⁺ +1)

NMR (δ, CDCl₃); 1.22 to 1.44 (3H, m), 1.61 to 1.74 (4H, m), 1.90 to 2.00(6H, m), 2.52 to 2.58 (2H, m), 2.79 to 2.98 (6H, m), 3.48 (2H, s), 6.52(1H, s), 7.25 to 7.32 (5H, m), 7.74 (2H, d, J=8.8 Hz), 7.96 (2H, d,J=8.8 Hz), 8.59 (1H, s)

EXAMPLE 11(E)-N-(7-methoxy-5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]aniline(Compound II-173 in Table 1)

(as 1/4H₂ O adduct)

White crystal

m.p. 193° to 195° C. (decomposed)

Mass; m/z=468 (M⁺)

NMR (δ, CDCl₃); 1.50 to 1.82 (4H, m), 2.00 to 2.38 (4H, m), 2.40 to 2.56(1H, m), 2.64 to 2.80 (1H, m), 2.90 to 3.12 (3H, m), 3.54 (2H, s), 3.58(3H, s), 4.72 to 4.77 (1H, m), 6.59 (1H, s), 6.87 (1H, d, J=15.6 Hz ),7.04 (1H, dd, J=6.4 Hz, 15.6 Hz), 7.26 to 7.34 (5H, m), 7.79 (2H, d,J=8.8 Hz ), 7.97 (2H, d, J=8.8 Hz), 8.75 (1H, s)

EXAMPLE 12N-(7-methoxy-5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline(Compound II-168 in Table 1)

(as 1/4H₂ O adduct)

White crystal

m.p. 178° to 180° C.

Mass; m/z=470 (M⁺)

NMR (δ, CDCl₃); 1.19 to 1.45 (3H, m), 1.60 to 1.81 (4H, m), 1.88 to 2.01(2H, m), 2.07 to 2.24 (1H, m), 2.39 to 2.60 (1H, m), 2.64 to 2.78 (1H,m), 2.85 to 3.02 (5H, m), 3.48 (2H, s), 3.58 (3H, s), 4.71 to 4.76 (1H,m), 6.52 (1H, s), 7.21 to 7.28 (5H, m), 7.76 (2H, d, J=8.8 Hz), 7.96(2H, d, J=8.8 Hz)

EXAMPLE 13(E)-N-(7-fluoro-5,6-dihydro-7H-cyclopenta[d]pyrimidin-yl)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]aniline(Compound II-188 in Table 1)

Pale yellow powder

Mass ; m/z=456 (M⁺)

NMR (δ, CDCl₃ -DMSO-d₆); 1.47 to 1.90 (4H, m), 1.96 to 2.16 (2H, m),1.86 to 2.16 (1H, m), 2.16 to 2.76 (3H, m), 2.76 to 3.23 (4H, m), 3.54(2H, s), 5.70 to 5.78 and 5.96 to 6.06 (total 1H, each m), 6.89 (1H, d,J=15 to 16 Hz), 7.02 (1H, dd, J=15 to 16 Hz, J=5 to 6 Hz), 7.18 to 7.40(5H, m), 7.86 to 8.04 (4H, m), 8.46 (1H, s), 8.74 (1H, s)

EXAMPLE 14N-(7-fluoro-5,6-dihydro-7H-cyclopenta[d]pyrimidin-4yl)-4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline·2HCl(2HCl salt of Compound II-183 in Table 1)

(as 1/2H₂ O adduct)

White crystal

m.p. 173° to 175° C.

Mass; m/z=458 (M⁺)

NMR (δ, CDCl₃ -DMSO-d₆); 1.55 to 1.98 (7H, m), 2.16 to 2.80 (2H, m),2.80 to 3.47 (8H, m), 4.30 (2H, d, J=4.9 Hz), 5.95 to 6.02 and 6.20 to6.31 (total 1H, each m), 7.36 to 7.53 (3H, m), 7.59 to 7.76 (2H, m),7.90 to 8.12 (4H, m), 8.88 (1H, s), 10.70 (1H, s), 10.88 (1H, br)

EXAMPLE 15(E)-N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-{3-[1-(4-methoxybenzyl)piperidin-4-yl]propenoyl}aniline(Compound II-29 in Table 1)

(as 1/2H₂ O adduct)

White powder

m.p. 198° to 199.5° C.

Mass; m/z=468 (M⁺)

NMR (δ, CDCl₃ -DMSO-d₆); 1.50 to 1.68 (2H, m), 1.76 to 1.82 (2H, m),2.00 to 2.28 (5H, m), 2.88 to 3.04 (6H, m), 3.47 (2H, s), 3.80 (3H, s),6.80 to 6.95 (3H, m), 7.01 (1H, dd, J=15.1 Hz, J=6.4 Hz), 7.23 (2H, d,J=8.3 Hz), 7.57 (1H, s), 7.84 (2H, d, J=8.8 Hz), 7.94 (2H, d, J=8.8 Hz),8.61 (1H, s)

EXAMPLE 16(E)-N-(5,6-diethylpyrimidin-4-yl)-4-[3-(1-benzyl-piperidin-4-yl)propenoyl]aniline(Compound II-200 in Table 1)

Pale yellow powder

Mass (CI); m/z=455 (M++i)

NMR (δ, CDCl₃); 1.20 to 1.38 (6H, m), 1.46 to 1.88 (4H, m), 1.96 to 2.16(2H, m), 2.15 to 2.40 (1H, m), 2.60 to 2.84 (4H, m), 2.88 to 3.02 (2H,m), 3.51 (2H, s), 6.71 (1H, s, br), 6.88 (1H, d, J=15 to 16 Hz), 7.04(1H, dd, J=15 to 16 Hz, J=6 to 7 Hz), 7.20 to 7.45 (5H, m), 7.35 (2H, d,J=8 to 9 Hz), 7.97 (2H, d, J=8 to 9 Hz), 8.64 (1H, s)

EXAMPLE 17(E)-N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-{3-[1-(4-fluorobenzyl)piperidin-4-yl]propenoyl}aniline(Compound II-11 in Table 1)

(as 1/2H₂ O adduct)

White powder

m.p. 209° to 210.5° C.

Mass; m/z=456 (M⁺)

NMR (δ, CDCl₃); 1.52 to 1.64 (2H, m), 1.80 to 1.84 (2H, m), 2.05 to 2.10(2H, m), 2.13 to 2.22 (2H, m), 2.23 to 2.31 (1H, m), 2.90 to 3.02 (6H,m), 3.49 (2H, s), 6.90 (1H, d, J=15.1 Hz), 6.92 to 7.03 (3H, m), 7.28 to7.30 (2H, m), 7.85 (1H, s), 7.88 (2H, d, J=8.8 Hz), 7.94 (2H, d, J=8.8Hz), 8.60 (1H, s)

EXAMPLE 18N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-{3-[1-(4-fluorobenzyl)piperidin-4-yl]propanoyl}aniline(Compound II-8 in Table 1)

(as 1/2H₂ O adduct)

Pale yellow powder

m.p. 179° to 181° C.

Mass; m/z=458 (M⁺)

NMR (δ, CDCl₃); 1.29 to 1.45 (3H, m), 1.66 to 1.80 (4H, m), 1.94 to 2.10(2H, m), 2.15 to 2.26 (2H, m), 2.82 to 3.05 (8H, m), 3.56 (2H, s, br),6.46 (1H, s), 6.96 to 7.05 (2H, m), 7.25 to 7.36 (2H, m), 7.78 (2H, d,J=8.8 Hz), 7.96 (2H, d, J=8.8 Hz), 8.66 (1H, s)

EXAMPLE 19(E)-N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-{3-[1-(3-fluorobenzyl)piperidin-4-yl]propenoyl}aniline(Compound II-17 in Table 1)

White powder

m.p. 210° to 211° C.

Mass (CI); m/z=457 (M⁺ +1)

NMR (δ, CDCl₃); 1.51 to 1.85 (4H, m), 2.02 to 2.30 (5H, m), 2.83 to 3.06(6H, m), 3.52 (2H, s), 6.46 (1H, s), 6.89 (1H, d, J=15.6 Hz), 6.95 to7.12 (4H, m), 7.23 to 7.35 (1H, m), 7.78 (2H, d, J=8.8 Hz), 7.98 (2H, d,J=8.8 Hz ), 8.66 (1H, s)

EXAMPLE 20N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-(3-[1-(3-fluorobenzyl)piperidin-4-yl]propanoyl)aniline·2HCl(2HCl salt of Compound II-14 in Table 1)

(as 3/2H₂ O adduct)

White powder

m.p.>252° C. (decomposed)

Mass (CI); 459 (M⁺ +1)

NMR (δ, CDCl₃); 1.24 to 1.40 (3H, m), 1.54 to 1.77 (4H, m), 1.89 to 2.02(2H, m), 2.15 to 2.25 (2H, m), 2.82 to 2.91 (4H, m), 2.91 to 3.05 (4H,m), 3.47 (2H, s), 6.45 (1H, s), 6.89 to 6.96 (1H, m), 7.02 to 7.11 (2H,m), 7.22 to 7.28 (1H, m), 7.76 (2H, d, J=8.8 Hz), 7.97 (2H, d, J=8.8Hz), 8.65 (1H, s)

EXAMPLE 214-[1-Oxo-2-(1-benzylpiperidin-4-yl)methyleneindan-5-yl]amino-5,6-dihydro-7H-cyclopenta[d]pyrimidine(Compound III-3 in Table 2)

Under ice cooling, 1.70 g of a 28% sodium methoxide·methanol solutionwas added to 1.96 g of4-(1-oxoindan-5-yl)amino-5,6-dihydro-7H-cyclopenta[d]pyrimidinedissolved in tetrahydrofuran, and then 1.80 g of1-benzyl-4-formylpiperidine was added dropwise thereto. After themixture was stirred for 1.5 hours, a saturated saline solution was addedto the reaction mixture, and the mixture was extracted with chloroform.The extract was dried over anhydrous sodium sulfate and condensed underreduced pressure. The obtained residue was applied to silica gel columnchromatography and then recrystallized from chloroform to obtain 1.35 gof the title compound as pale yellow crystal.

(as 1/2H₂ O adduct)

m.p.>260° C. (decomposed)

Mass; m/z=450 (M⁺)

NMR (δ, CDCl₃); 1.45 to 1.85 (4H, m), 1.96 to 2.46 (5H, m), 2.80 to 3.10(6H, m), 3.56 (2H, s), 3.70 (2H, s), 6.55 (1H, s), 6.70 (1H, d, J=9.8Hz), 7.24 to 7.41 (6H, m), 7.82 (1H, d, J=5.3 Hz), 8.18 (1H, s), 8.66(1H, s)

EXAMPLE 224-[1-Oxo-2-(1-benzylpiperidin-4-yl)methylindan-5-yl]amino-5,6-dihydro-7H-cyclopenta[d]pyrimidine(Compound III-4 in Table 2)

0.53 g of platinum oxide was added to 1.35 g of4-[1-oxo-2-(1-benzylpiperidin-4-yl)methyleneindan-5-yl]amino-5,6-dihydro-7H-cyclopenta[d]pyrimidinedissolved in a mixed solution of 60 ml of tetrahydrofuran, 60 ml ofethanol and 1 ml of acetic acid, and the mixture was stirred under ahydrogen stream at room temperature for 8 hours. After the catalyst wasremoved by filtration, the filtrate was condensed. The obtained residuewas applied to silica gel column chromatography to obtain 1.31 g of thetitle compound as pale yellow powder.

m.p. 200° to 202° C.

Mass; m/z=452 (M⁺)

NMR (δ, CDCl₃); 1.18 to 2.12 (9H, m), 2.12 to 2.30 (2H, m), 2.62 to 3.08(8H, m), 3.25 to 3.44 (1H, m), 3.55 (2H, s), 6.49 (1H, s), 7.20 to 7.41(6H, m), 7.71 (1H, d, J=8.3 Hz), 8.10 (1H, d, J=1 to 2 Hz), 8.66 (1H, s)

EXAMPLE 23N-(5-ethylpyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline(Compound II-205 in Table 1)

To 10 ml of ethanol were added 0.23 g of4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline and 0.13 g of4-chloro-5-ethylpyrimidine, and after adding 2 ml of an ethanol solutionof hydrochloric acid (containing 0.071 g of hydrochloric acid), themixture was reacted under reflux for 2 hours. After cooling, a 28%sodium methylate-methanol solution was added to the reaction mixture tomake it alkaline, and then the mixture was condensed under reducedpressure. The obtained residue was applied to silica gel columnchromatography to obtain 0.18 g of the title compound as pale yellowcrystal.

m.p. 136.5° to 138° C.

Mass (CI); m/z=429 (M⁺ +1)

NMR (δ, CDCl₃); 1.24 to 1.43 (3H, m), 1.37 (3H, t, J=7.3 Hz), 1.56 to1.80 (4H, m), 1.87 to 2.05 (2H, m), 2.61 (2H, q, J=7.3 Hz), 2.81 to 3.00(4H, m), 3.51 (2H, s), 6.63 (1H, s, br), 7.18 to 7.37 (5H, m), 7.77 (2H,d, J=9.2 Hz), 7.98 (2H, d, J=9.2 Hz), 8.27 (1H, s), 8.71 (1H, s)

EXAMPLE 24N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-{3-[1-(2-nitrobenzyl)piperidin-4-yl]propanoyl}aniline(Compound II-242 in Table 1)

(1)N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3(1-acetylpiperidin-4-yl)propanoyl]aniline

To 80 ml of chloroform were added 4.53 g of4-[3-(1-acetylpiperidin-4-yl)propanoyl]aniline and 3.83 g of4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine, and after adding 10 mlof a chloroform solution of hydrochloric acid (containing 0.9 g ofhydrochloric acid), the mixture was refluxed under heating for 5 hours.After completion of the reaction, a 28% sodium methoxide was added tothe mixture under ice cooling to make it alkaline and then the solventwas removed by distillation under reduced pressure. The obtained residuewas applied to silica gel column chromatography to obtain 6.16 g of thetitle compound as brown powder.

Mass; m/z=392 (M⁺)

NMR (δ, CDCl₃ -DMSO-d₆); 1.00 to 1.27 (2H, m), 1.52 to 1.87 (5H, m),2.05 (3H, s), 2.03 to 2.23 (2H, m), 2.45 to 2.61 (2H, m), 2.87 to 3.11(6H, m), 3.76 to 3.89 (1H, m), 4.46 to 4.58 (1H, m), 7.86 to 7.96 (4H,m), 8.51 (1H, s), 8.70 (1H, s)

(2)N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3-(piperidin-4-yl)propanoyl]aniline·2HClsalt

30 ml of conc. hydrochloric acid was added to 6.16 g ofN-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3-(1-acetylpiperidin-4-yl)propanoyl]aniline,and after refluxing under heating for 7 hours, the mixture was condensedunder reduced pressure. The obtained residue was washed with methanol toobtain 3.38 g of the title compound as yellow powder.

Mass; m/z=350 (M⁺)

NMR (δ, CD₃ OD); 1.36 to 1.56 (2H, m), 1.64 to 1.83 (3H, m), 1.95 to2.09 (2H, m), 2.92 to 3.24 (8H, m), 3.35 to 3.46 (2H, m), 7.08 to 7.25(1H, m), 7.90 (2H, d, J=9.2 Hz), 8.08 (2H, d, J=9.2 Hz), 8.75 (1H, s)(3)N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-{3-[1(2-nitrobenzyl)piperidin-4-yl]acetyl}aniline

30 ml of acetone, 7.12 g of potassium carbonate and 0.62 g of2-nitrobenzyl bromide were added to 1.00 g ofN-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3-(piperidin-4-yl]propanoyl]aniline·2HClsalt, and the mixture was stirred at room temperature for 2 hours andallowed to stand overnight. Then, after separating the solid byfiltration and removing the solvent by distillation under reducedpressure, the obtained residue was applied to silica gel columnchromatography to obtain 0.72 g of the title compound as white powder.

m.p. 164° to 166° C.

Mass (SIMS); m/z=486 (M⁺ +1)

NMR (δ, CDCl₃); 1.16 to 1.40 (3H, m), 1.52 to 1.77 (4H, m), 1.94 to 2.08(2H, m), 2.09 to 2.27 (2H, m), 2.72 to 3.06 (8H, m), 3.75 (2H, s), 6.47(1H, s), 7.32 to 7.43 (1H, m), 7.48 to 7.59 (1H, m), 7.60 to 7.68 (1H,m), 7.76 (2H, d, J=8.5 Hz), 7.74 to 7.83 (1H, m), 7.96 (2H, d, J=9.2Hz), 8.65 (1H, s)

EXAMPLE 25N-(5-methylpyrimidin-4-yl)-4-[(1-benzylpiperidin-4-yl)acetyl]aniline(Compound II-220 in Table 1)

To 70 ml of chloroform were added 7.00 g of4-[(1-benzylpiperidin-4-yl)acetyl]aniline·2HCl salt and 8.38 g of4-chloro-5-methylpyrimidine, and after further adding 10 ml of anethanol solution of hydrochloric acid (containing 1.7 g of hydrochloricacid), the mixture was reacted under reflux for 5 hours. After thereaction, a 28% sodium methylate-methanol solution was added to thereaction mixture to make it alkaline and then the mixture was condensedunder reduced pressure. The obtained residue was applied to silica gelcolumn chromatography to obtain 5.30 g of the title compound as paleyellow crystal.

m.p. 211° to 213° C.

Mass; m/z=400 (M⁺)

NMR (δ, CDCl₃); 1.26 to 1.47 (2H, m), 1.63 to 1.80 (3H, m), 1.89 to 2.08(2H, m), 2.25 (3H, s), 2.76 to 2.93 (4H, m), 3.48 (2H, s), 6.58 (1H, s,br), 7.17 to 7.38 (5H, m), 7.78 (2H, d, J=8.6 Hz), 7.97 (2H, d, J=8.6Hz), 8.24 (1H, s), 8.70 (1H, s)

EXAMPLE 26N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(1-benzylpiperidin-4-yl)acetyl]aniline(Compound II-1 in Table 1)

(1)N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(1-acetylpiperidin-4-yl)acetyl]aniline

To 50 ml of chloroform were added 6.63 g of4-[(1-acetylpiperidin-4-yl)acetyl]aniline·trifluoroacetate and 3.01 g of4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine, and after adding 10 mlof a chloroform solution of hydrochloric acid (containing 0.6 g ofhydrochloric acid), the mixture was reacted under reflux for 3 hours.After the reaction, a 28% sodium methylate-methanol solution was addedto the reaction mixture under cooling to make it alkaline. Afterremoving solid material, the filtrate was condensed under reducedpressure and the obtained residue was applied to silica gel columnchromatography to obtain 6.08 g of the title compound as yellowish whitepowder.

m.p. 225° to 227° C.

Mass (CI); m/z=379 (M⁺ +1)

NMR (δ, CDCl₃); 1.12 to 1.33 (2H, m), 1.72 to 1.92 (2H, m), 2.04 to 2.35(3H, m), 2.09 (3H, s), 2.52 to 2.68 (1H, m), 2.68 to 2.93 (4H, m), 2.93to 3.18 (3H, m), 3.94 to 4.12 (1H, m), 4.55 to 4.70 (1H, m), 6.65 (1H,s, br), 7.79 (2H, d, J=8.8 Hz), 7.89 (2H, d, J=8.8 Hz), 8.65 (1H, s) (2)N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(piperidin-4-yl)acetyl]aniline·2HClsalt

50 ml of conc. hydrochloric acid was added to 6.08 g ofN-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(1-acetylpiperidin-4-yl)acetyl]aniline,and after refluxing the mixture under heating, the solvent was removedby distillation under reduced pressure. The obtained solid was washedwith hot-ethanol to obtain 5.13 g of the title compound as yellowishwhite powder.

Mass (CI); m/z=337 (M⁺ +1)

NMR (δ, CDCl₃ -DMSO-d₆); 1.48 to 1.69 (2H, m), 1.84 to 2.00 (2H, m),2.10 to 2.35 (3H, m), 2.72 to 3.21 (8H, m), 3.21 to 3.38 (2H, m), 7.92(2H, d, J=9.2 Hz), 7.99 (2H, d, J=8.6 Hz), 8.84 (1H, s), 10.64 (1H, s)

(3)N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(1-benzylpiperidin-4-yl)acetyl]aniline

50 ml of acetone, 1.14 g of potassium carbonate and 0.4 ml of benzylbromide were added to 1.34 g ofN-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(piperidin-4-yl)acetyl]aniline,and the mixture was stirred at room temperature for 4 hours. Afterseparating the solid by filtration and removing the solvent bydistillation under reduced pressure, the obtained residue was applied tosilica gel column chromatography to obtain 1.05 g of the title compoundas yellowish white powder.

m.p. 212° to 214° C. (decomposed)

Mass; m/z=426 (M⁺)

NMR (δ, CDCl₃); 1.28 to 1.48 (2H, m), 1.67 to 1.80 (2H, m), 1.90 to 2.09(3H, m), 2.12 to 2.28 (2H, m), 2.79 to 2.90 (6H, m), 2.98 to 3.05 (2H,m), 3.49 (2H, s), 6.42 (1H, s), 7.20 to 7.38 (5H, m), 7.77 (2H, d, J=8.8Hz), 7.96 (2H, d, J=8.8 Hz), 8.66 (1H, s)

EXAMPLE 27N-(5-methylpyrimidin-4-yl)-4-{[1-(2-pyridylmethyl)piperidin-4-yl]acetyl}aniline(Compound II-219 in Table 1)

In the same manner as in Example 26-(1), (2) and (3) except for using4-chloro-5-methylpyrimidine in place of4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine and using2-chloromethylpyridine in place of benzyl bromide in Example 26-(1), (2)and (3), the following compounds were obtained, respectively.

(1) N-(5-methylpyrimidin-4-yl)-4-[(1-acetylpiperidin-4yl)acetyl]aniline

Yellowish white solid

Mass (CI); m/z=353 (M⁺ +1)

NMR (δ, CDCl₃); 1.12 to 1.30 (2H, m), 1.73 to 1.93 (3H, m), 2.08 (3H,s), 2.26 (3H, s), 2.52 to 2.67 (1H, m), 2.84 to 2.93 (2H, m), 3.02 to3.17 (1H, m), 3.73 to 3.86 (1H, m), 4.54 to 4.67 (1H, m), 6.92 (1H, s),7.82 (2H, d, J=8.6 Hz), 7.97 (2H, d, J=9.2 Hz), 8.24 (1H, s), 8.69 (1H,s)

(2) N- (5-methylpyrimidin-4-yl)-4-[(piperidin-4-yl)acetyl]aniline

Yellowish white solid

Mass (CI); m/z=311 (M⁺ +1)

NMR (δ, CDCl₃); 1.46 to 1.70 (2H, m), 1.82 to 1.98 (3H, m), 2.42 (3H,s), 2.83 to 3.09 (2H, m), 3.02 (2H, d, J=6.7 Hz), 3.21 to 3.38 (2H, m),7.85 (2H, d, J=8.5 Hz), 8.02 (2H, d, J=8.5 Hz), 8.43 (1H, s), 8.86 (1H,s), 10.36 (1H, s)

(3)N-(5-methylpyrimidin-4-yl)-4-{[1-(2-pyridylmethyl)piperidin-4-yl]acetyl}aniline

White crystal

m.p. 207° to 209° C.

Mass (CI); m/z=402 (M⁺ +1)

NMR (δ, CDCl₃); 1.33 to 1.50 (2H, m), 1.66 to 1.81 (2H, m), 1.81 to 1.94(1H, m), 2.07 to 2.20 (2H, m), 2.52 (3H, s), 2.86 (2H, d, J=6.7 Hz),2.78 to 2.95 (2H, m), 3.64 (2H, s), 6.63 (1H, s), 7.11 to 7.20 (1H, m),7.40 (1H, d, J=7.3 Hz), 7.61 to 7.70 (1H, m), 7.79 (2H, d, J=8.5 Hz),7.98 (2H, d, J=9.2 Hz), 8.25 (1H, s), 8.55 (1H, d, J=4.8 Hz), 8.70 (1H,s)

EXAMPLE 28(E)-N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[4-(1-benzylpiperidin-4-yl)-2-butenoyl]aniline(Compound II-6 in Table 1)

30 ml of ethanol and 0.58 g of4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine were added to 1.21 g of4-[4-(1-benzylpiperidin-4-yl)-3-hydroxybutanoyl]aniline·trifluoroacetate,1 ml of an ethanol solution of hydrochloric acid (containing 0.29 g ofhydrochloric acid) was added thereto and the mixture was stirred underheating at 60° C. for 40 minutes. Then, a saturated sodium hydrogencarbonate aqueous solution was added thereto and the mixture wasextracted with chloroform. After drying over anhydrous sodium sulfate,the solvent was removed by distillation under reduced pressure and theobtained residue was applied to silica gel column chromatography toobtain 0.40 g of the title compound as yellow powder.

m.p. 184° to 185° C.

Mass (CI); m/z=453 (M⁺ +1)

NMR (δ, CDCl₃); 1.24 to 1.60 (3H, m), 1.60 to 1.82 (2H, m), 1.88 to 2.05(2H, m), 2.10 to 2.34 (4H, m), 2.80 to 2.98 (4H, m), 2.98 to 3.08 (2H,m), 3.50 (2H, s), 6.48 (1H, s, br), 6.90 (1H, d, J=16.9 Hz), 6.98 to7.12 (1H, m), 7.12 to 7.41 (5H, m), 7.78 (2H, d, J=8.8 Hz), 7.97 (2H, d,J=8.8 Hz), 8.66 (1H, s)

EXAMPLE 29N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[4-(1-benzylpiperidin-4-yl)butanoyl]aniline(Compound II-3 in Table 1)

30 ml of ethanol and 0.1 g of platinum oxide were added to 0.24 g of(E)-N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[4-(1-benzylpiperidin-4-yl)-2-butenoyl]aniline,and the mixture was stirred at room temperature under a hydrogen streamfor 45 minutes. After removing the solid by filtration, the solvent wasremoved by distillation and the obtained residue was applied to silicagel column chromatography to obtain 0.19 g of the title compound aswhite powder.

m.p. 170° to 173° C.

Mass (CI); m/z=455 (M⁺ +1)

NMR (δ, CDCl₃); 1.14 to 1.38 (5H, m), 1.56 to 1.83 (6H, m), 1.83 to 2.01(2H, m), 2.14 to 2.27 (2H, m), 2.85 to 2.96 (4H, m), 2.96 to 3.06 (2H,m), 3.49 (2H, s), 6.42 (1H, s, br), 7.19 to 7.35 (5H, m), 7.76 (2H, d,J=8.8 Hz), 7.97 (2H, d, J=8.8 Hz), 8.65 (1H, s)

EXAMPLE 30

(a)N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4[(1-benzyl-4-hydroxypiperidin-4-yl)acetyl]aniline(Compound II-216 in Table 1),

(b)N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4[(1-benzyl-4-ethoxypiperidin-4-yl)acetyl]aniline(Compound II-215 in Table 1) and

(c)N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4[(1-benzyl-1,2,5,6-tetrahydropyridin-4-yl)acetyl]aniline(Compound II-217 in Table 1)

30 ml of ethanol and 0.59 g of4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine were added to 1.04 g of4-[(1-benzyl-4-hydroxypiperidin-4-yl)acetyl]aniline·trifluoroacetate,then 1 ml of an ethanol solution of hydrochloric acid (containing 0.29 gof hydrochloric acid) was added to the mixture and the mixture wasstirred at 60° C. for 45 minutes. Thereafter, 1 ml of triethylamine andwater were added thereto, and the reaction mixture was extracted withchloroform and dried over anhydrous sodium sulfate. After removing thesolvent by distillation under reduced pressure, the obtained residue wasapplied to silica gel column chromatography to obtain 0.60 g, 0.23 g and0.05 g of the title compounds (a), (b) and (c), respectively.

Compound of (a)

Yellowish white crystal

m.p. 193° to 195° C.

Mass (CI); m/z=443 (M⁺ +1)

NMR (δ, CDCl₃); 1.62 to 1.88 (4H, m), 2.12 to 2.30 (2H, m), 2.42 to 2.58(2H, m), 2.58 to 2.72 (2H, m), 2.86 (2H, t, J=7.3 Hz), 2.93 to 3.06 (2H,m), 3.08 (2H, s), 3.56 (2H, s), 4.14 (2H, s), 6.49 (1H, s, br), 7.21 to7.38 (5H, m), 7.79 (2H, d, J=8.6 Hz), 7.95 (2H, d, J=8.6 Hz), 8.66 (1H,s)

Compound of (b)

Yellowish white crystal

m.p. 142° to 143° C.

Mass (CI); m/z=471 (M⁺ +1)

NMR (δ, CDCl₃); 1.13 (3H, t, J=7.7 Hz), 1.74 to 1.95 (4H, m), 2.13 to2.28 (2H, m), 2.28 to 2.44 (2H, m), 2.54 to 2.70 (2H, m), 2.85 (2H, t,J=7.3 Hz), 3.01 (2H, t, J=7.9 Hz), 3.10 (2H, s), 3.40 to 3.48 (2H, m),3.51 (2H, s, br), 6.43 (1H, s), 7.18 to 7.38 (5H, m), 7.76 (2H, d, J=8.5Hz), 7.96 (2H, d, J=9.2 Hz), 8.65 (1H, s)

Compound of (c)

Pale yellow crystal

m.p. 165° to 167° C.

Mass; 424 (M⁺)

NMR (δ, CDCl₃); 2.12 to 2.28 (4H, m), 2.53 to 2.66 (2H, m), 2.78 to 2.91(2H, m), 2.91 to 3.08 (4H, m), 3.60 (2H, s), 3.61 (2H, s), 5.54 (1H, s,br), 6.47 (1H, s), 7.20 to 7.59 (5H, m), 7.77 (2H, d, J=8.5 Hz), 7.99(2H, d, J=8.5 Hz), 8.65 (1H, s)

EXAMPLE 31N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(1-benzyl-4-piperidinyliden)acetyl]aniline(Compound II-4 in Table 1)

To a mixed solvent of 40 ml of chloroform and 20 ml of ethanol wereadded 2.33 g of 4-[(1-benzyl-4-piperidinyliden)acetyl]aniline and 1.63 gof 4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine, and further 6 ml ofan ethanol solution of hydrochloric acid (containing 0.4 g ofhydrochloric acid) was added to the mixture and the mixture was stirredat 50° to 60° C. for 3.5 hours under heating. Then, under ice cooling, a28% sodium methylate-methanol solution was added to the mixture to makeit alkaline, and then the solvent was removed by distillation underreduced pressure and the obtained residue was applied to silica gelcolumn chromatography to obtain 0.3 g of the title compound as yellowishwhite powder.

Mass (CI); m/z=425 (M⁺ +1)

NMR (δ, CDCl₃); 2.13 to 2.24 (2H, m), 2.40 to 2.51 (2H, m), 2.51 to 2.65(4H, m), 2.75 to 2.90 (2H, m), 2.90 to 3.06 (4H, m), 3.54 (2H, s), 6.50(1H, s), 6.64 (1H, s), 7.18 to 7.43 (5H, m), 7.61 (2H, d, J=9.2 Hz),7.95 (2H, d, J=8.5 Hz), 8.65 (1H, s)

EXAMPLE 32N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-{3-[1-(2-thienylmethyl)piperidin-4-yl]propanoyl}aniline·2HCl

(2HCl salt of Compound II-104 in Table 1)

30 ml of 1,2-dichloroethane and 0.07 ml of triethylsilane were added to0.20 g ofN-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-{3-[1-(2-thienylmethyl)piperidin-4-yl]propenoyl}aniline,then 0.35 ml of trifluoroacetic acid was added to the mixture and themixture was stirred at 50° C. for 3 hours under heating. After thereaction, the solvent was removed by distillation under reducedpressure, a 1N sodium hydroxide aqueous solution was added to theresidue and the residue was extracted with chloroform. After drying overanhydrous sodium sulfate, the solvent was removed by distillation underreduced pressure and the obtained residue was applied to silica gelcolumn chromatography to obtain an ocherous solid. The solid wasrecrystallized form isopropyl alcohol and further treated withhydrochloric acid to obtain 0.05 g of the title compound as whitepowder.

(as 3/4H₂ O adduct)

m.p. 187° C. (decomposed)

Mass (CI); m/z=447 (M⁺ +1)

NMR (δ, CDCl₃); 1.14 to 1.46 (2H, m), 1.46 to 1.84 (5H, m), 1.88 to 2.12(2H, m), 2.12 to 2.20 (2H, m), 2.74 to 3.10 (8H, m), 3.70 to 3.85 (2H,m), 6.40 (1H, s), 6.87 to 7.02 (2H, m), 7.16 to 7.20 (6H, m), 7.76 (2H,d, J=9.2 Hz), 7.97 (2H, d, J=8.5 Hz), 8.65 (1H, s)

EXAMPLE 33N-(7-hydroxy-5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline(Compound II-167 in Table 1)

To 15 ml of ethanol were added 0.60 g of4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline and 0.51 g of7-acetoxy-4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine, then 3 ml ofan ethanol solution of hydrochloric acid (containing 0.19 g ofhydrochloric acid) was added to the mixture and the mixture was reactedunder reflux for 30 minutes. After cooling, a 28% sodiummethylate-methanol solution was added to the reaction mixture to make italkaline, and the mixture was condensed under reduced pressure. Theobtained residue was applied to silica gel column chromatography toobtain 0.49 g of the title compound as white crystal.

m.p. 189° to 190° C.

Mass; m/z=456 (M⁺)

NMR (δ, CDCl₃ -DMSO-d₆); 1.21 to 1.45 (3H, m), 1.56 to 1.81 (4H, m),1.86 to 2.11 (3H, m), 2.47 to 3.08 (7H, m), 3.50 (2H, s), 4.83 (1H, br),5.05 to 5.17 (1H, m), 7.16 to 7.38 (5H, m), 7.87 (2H, d, J=8.8 Hz), 7.94(2H, d, J=8.8 Hz), 8.16 (1H, s), 8.68 (1H, s)

EXAMPLE 34N-(7-hydroxy-5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(1-benzylpiperidin-4-yl)acetyl]aniline(Compound II-236 in Table 1)

In the same manner as in Example 33 except for using4-[1-benzylpiperidin-4-yl)acetyl]aniline in place of4-[3(1-benzylpiperidin-4-yl)propanoyl]aniline, the reaction was carriedout to obtain the tile compound as white crystal.

m.p. 174° to 176° C.

Mass; m/z=442 (M⁺)

NMR (δ, CDCl₃ -DMSO-d₆); 1.18 to 1.48 (3H, m), 1.66 to 1.80 (2H, m),1.88 to 2.13 (4H, m), 2.50 to 2.66 (1H, m), 2.66 to 3.05 (3H, m), 2.85(2H, d, J=6.7 Hz), 3.49 (2H, s), 5.09 to 5.20 (1H, m), 7.18 to 7.43 (6H,m), 7.85 (2H, d, J=9.2 Hz), 7.95 (2H, d, J=9.2 Hz), 8.69 (1H, s)

EXAMPLE 35N-(7-acetoxy-5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(1-benzylpiperidin-4-yl)acetyl]aniline(Compound II-237 in Table 1)

20 ml of chloroform and 0.65 ml of acetic anhydride were added to 0.35 gofN-(7-hydroxy-5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(1-benzylpiperidin-4-yl)acetyl]aniline,and the mixture was refluxed under heating for 4 hours. Then, thesolvent was removed by distillation under reduced pressure and theobtained residue was applied to silica gel column chromatography toobtain 0.16 g of the title compound as white crystal.

(as 1/2H₂ O adduct)

m.p. 210° to 212° C.

Mass; m/z=484 (M⁺)

NMR (δ, CDCl₃); 1.29 to 1.47 (3H, m), 1.54 to 1.63 (2H, m), 1.68 to 1.94(4H, m), 2.15 (3H, s), 2.67 to 3.04 (4H, m), 2.86 (2H, d, J=6.7 Hz),3.50 (2H, s, br), 6.07 to 6.14 (1H, m), 6.53 (1H, s), 7.19 to 7.34 (5H,m), 7.78 (2H, d, J=9.2 Hz), 7.98 (2H, d, J=8.6 Hz), 8.78 (1H, s)

EXAMPLE 36N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-{3-[1-(2-aminobenzyl)piperidin-4-yl]propanoyl}aniline(Compound II-272 in Table 1)

To 0.59 g of N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-3-[1-(2-nitrobenzyl)piperidin-4-yl]propanoyl)anilinewere added 20 ml of ethanol, 40 ml of methanol, 5 ml of acetic acid and0.05 g of platinum oxide, and the mixture was stirred at roomtemperature under a hydrogen stream for 4 hours. Then, after the solidwas removed by filtration and the solvent was removed by distillationunder reduced pressure, a saturated sodium hydrogen carbonate aqueoussolution was added to the residue and the mixture was extracted withchloroform. The solvent was removed by distillation under reducedpressure and the obtained solid was recrystallized from ethanol toobtain 0.32 g of the title compound as pale brown crystal.

Mass; m/z=455 (M⁺)

NMR (δ, CDCl₃); 1.12 to 1.32 (3H, m), 1.56 to 1.77 (4H, m), 1.83 to 1.98(2H, m), 2.14 to 2.28 (2H, m), 2.79 to 3.07 (8H, m), 3.47 (2H, s), 4.81(2H, s, br), 6.43 (1H, s, br), 6.62 to 6.68 (2H, m), 6.97 (1H, d, J=6.7Hz), 7.05 to 7.11 (1H, m), 7.76 (2H, d, J=8.5 Hz), 7.97 (2H, d, J=9.2Hz), 8.65 (1H, s)

EXAMPLE 37 N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-{3-[1-(2-acetylaminobenzyl)piperidin-4-yl]propanoyl}aniline(Compound II-249 in Table 1)

To 0.17 g ofN-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-(3-[1-(2-aminobenzyl)piperidin-4-yl]propanoyl)anilinewere added 30 ml of chloroform, 1 ml of acetic anhydride and 0.38 g of4-dimethylaminopyridine, and the mixture was stirred at 50° C. for 10minutes. Then, the solvent was removed by distillation under reducedpressure and the obtained residue was applied to silica gel columnchromatography to obtain 0.06 g of the title compound as white crystal.

m.p. 219° to 221.5° C.

Mass; m/z=497 (M⁺)

NMR (δ, CDCl₃); 1.14 to 1.34 (2H, m), 1.34 to 1.50 (1H, m), 1.66 to 1.89(4H, m), 1.96 to 2.10 (2H, m), 2.14 (3H, s), 2.11 to 2.28 (2H, m), 2.80to 3.08 (8H, m), 3.57 (2H, s), 6.44 (1H, s), 6.94 to 7.01 (1H, m), 7.25(2H, d, J=6.1 Hz), 7.23 to 7.31 (1H, m), 7.78 (2H, d, J=8.5 Hz), 7.97(2H, d, J=9.2 Hz), 8.27 (1H, d, J=8.6 Hz), 8.65 (1H, s), 11.04 (1H, s)

EXAMPLE 38N-acetyl-N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4yl)-4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline·2HCl(2HCl salt of Compound II-221 in Table 1)

To 10 ml of a chloroform solution containing 0.72 g ofN-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline were added under icecooling 0.66 g of triethylamine and 0.46 ml of acetyl chloride. Afterstirring under ice cooling for one hour, a saturated saline solution wasadded to the mixture and the mixture was extracted with chloroform. Thechloroform layer was dried over anhydrous sodium sulfate and condensedunder reduced pressure. The obtained residue was applied to silica gelcolumn chromatography to obtain the free material of the title compound.This material was dissolved in ethyl acetate and treated with a hydrogenchloride gas to obtain 0.54 g of the title compound as pale browncrystal.

(as H₂ O adduct)

m.p. 128° to 131.5° C.

Mass (CI); m/z=483 (M⁺ +1)

NMR (δ, CDCl₃); 1.52 to 1.96 (5H, m), 2.00 to 2.38 (4H, m), 2.23 (3H,s), 2.53 to 2.86 (4H, m), 2.93 to 3.12 (2H, m), 3.34 to 3.57 (4H, m),4.16 (2H, d, J=4.4 Hz), 7.35 (2H, d, J=8.1 Hz), 7.40 to 7.53 (3H, m),7.57 to 7.70 (2H, m), 8.08 (2H, d, J=8.1 Hz), 8.83 (1H, s), 12.25 (1H,s, br)

EXAMPLES 39 TO 78

In the same manner as in Example 1, 2, 3, 23, 24 or 36, the followingcompounds were obtained.

    ______________________________________                                        Exam-                      Characteristics.                                   ple   Compound             Physical properties                                ______________________________________                                        39    N-(5,6-dihydro-7H-cyclopenta-                                                                      (as 3/2H.sub.2 O adduct)                                 [d]pyrimidin-4-yl)-4-{3-[1-(2-                                                                     White powder                                             fluorobenzyl)piperidin-4-yl]-                                                                      m.p. 205 to 209° C.                               propanoyl}aniline.2HCl (2HCl salt                                                                  (decomposed)                                             of Compound II-20 in Table 1)                                           40    N-(5,6-dihydro-7H-cyclopenta-                                                                      White powder                                             [d]pyrimidin-4-yl)-4-{3-[1-(4-                                                                     m.p. 213 to 216° C.                               chlorobenzyl)piperidin-4-yl]-                                                 propanoyl}aniline (Compound II-                                               50 in Table 1)                                                          41    N-(5,6-dihydro-7H-cyclopenta-                                                                      (as 1/4H.sub.2 O adduct)                                 [d]pyrimidin-4-yl)-4-{3-[1-(3-                                                                     Yellow crystal                                           chlorobenzyl)piperidin-4-yl]-                                                                      m.p. 189 to 191° C.                               propanoyl}aniline.2HCl (2Hcl salt                                             of Compound II-56 in Table 1)                                           42    N-(5,6-dihydro-7H-cyclopenta-                                                                      (as 1/2H.sub.2 O adduct)                                 [d]pyrimidin-4-yl)-4-{3-[1-(3-                                                                     Yellowish white                                          methoxybenzyl)piperidin-4-yl]-                                                                     powder                                                   propanoyl}aniline.2HCl (2HCl salt                                                                  m.p. 186 to 188° C.                               of Compound II-32 in Table 1)                                           43    N-(5,6-dihydro-7H-cyclopenta-                                                                      Yellowish white                                          [d]pyrimidin-4-yl)-4-{3-[1-(2-                                                                     powder                                                   methoxybenzyl)piperidin-4-yl]-                                                                     m.p. 169.5 to 172                                        propanoyl}aniline (Compound II-                                                                    °C.                                               38 in Table 1)                                                          44    N-(5,6-dihydro-7H-cyclopenta-                                                                      (as 1/2H.sub.2 O adduct)                                 [d]pyrimidin-4-yl)-4-{3-[1-(3-                                                                     Yellowish white                                          benzyloxybenzyl)piperidin-4-                                                                       powder                                                   yl]propanoyl}aniline (Compound                                                                     m.p. 193 to 195° C.                               II-239 in Table 1)                                                      45    N-(5,6-dihydro-7H-cyclopenta-                                                                      Yellowish white                                          [d]pyrimidin-4-yl)-4-{3-[1-(4-                                                                     powder                                                   methylbenzyl)piperidin-4-yl]-                                                                      m.p. 192 to 195° C.                               propanoyl}aniline.HCl (HCl salt                                                                    (decomposed)                                             of Compound II-68 in Table 1)                                           46    N-(5,6-dihydro-7H-cyclopenta-                                                                      (as 1/2H.sub.2 O adduct)                                 [d]pyrimidin-4-yl)-4-{3-[1-(3-                                                                     White powder                                             methylbenzyl)piperidin-4-yl]-                                                                      m.p. 116 to 117.5                                        propanoyl}aniline (Compound II-                                                                    °C.                                               214 in Table 1)                                                         47    N-(5,6-dihydro-7H-cyclopenta-                                                                      (as 1/4H.sub.2 O adduct)                                 [d]pyrimidin-4-yl)-4-{3-[1-(4-                                                                     Yellowish white                                          trifluoromethylbenzyl)piperi-                                                                      crystal                                                  din-4-yl]propanoyl}aniline                                                                         m.p. 216 to 218° C.                               (Compound II-80 in Table 1)                                             48    N-(5,6-dihydro-7H-cyclopenta-                                                                      Yellow crystal                                           [d]pyrimidin-4-yl)-4-{3-[1-(3-                                                                     m.p. 209 to 211.5                                        trifluoromethylbenzyl)piperi-                                                                      °C.                                               din-4-yl]propanoyl}aniline                                                    (Compound II-232 in Table 1)                                            49    N-(5,6-dihydro-7H-cyclopenta-                                                                      White powder                                             [d]pyrimidin-4-yl)-4-{3-[1-(4-                                                                     m.p. 180 to 182.5                                        cyanobenzyl)piperidin-4-yl]-                                                                       °C.                                               propanoyl}aniline (Compound II-                                               218 in Table 1)                                                         50    N-(5,6-dihydro-7H-cyclopenta-                                                                      White powder                                             [d]pyrimidin-4-yl)-4-{3-[1-(3-                                                                     m.p. 188 to 190° C.                               cyanobenzyl)piperidin-4-yl]-                                                                       (decomposed)                                             propanoyl}aniline (Compound II-                                               225 in Table 1)                                                         51    N-(5,6-dihydro-7H-cyclopenta-                                                                      White powder                                             [d]pyrimidin-4-yl)-4-{3-[1-(1-                                                                     m.p. 197 to 199° C.                               naphthylmethyl)piperidin-4-yl]-                                               propanoyl}aniline (Compound II-                                               224 in Table 1)                                                         52    N-(5,6-dihydro-7H-cyclopenta-                                                                      Pale yellow crystal                                      [d]pyrimidin-4-yl)-4-{3-[1-                                                                        m.p. 190 to 193° C.                               (sec-phenethyl)piperidin-4-yl]-                                                                    (decomposed)                                             propanoyl}aniline (Compound II-                                               86 in Table 1)                                                          53    N-(5,6-dihydro-7H-cyclopenta-                                                                      Yellow crystal                                           [d]pyrimidin-4-yl)-4-{3-[1-(2-                                                                     m.p. 181.5 to 183                                        pyridylmethyl)piperidin-4-yl]-                                                                     °C.                                               propanoyl}aniline (Compound II-                                               110 in Table 1)                                                         54    N-(5,6-dihydro-7H-cyclopenta-                                                                      Pale brown crystal                                       [d]pyrimidin-4-yl)-4-{3-[1-(3-                                                                     m.p. 167 to 169° C.                               pyridylmethyl)piperidin-4-yl]-                                                propanoyl}aniline (Compound II-                                               210 in Table 1)                                                         55    N-(5,6-dihydro-7H-cyclopenta-                                                                      (as 1/4H.sub.2 O adduct)                                 [d]pyrimidin-4-yl)-4-{3-[1-(4-                                                                     Pale brown crystal                                       pyridylmethyl)piperidin-4-yl]-                                                                     m.p. 174 to 175° C.                               propanoyl}aniline (Compound II-                                               116 in Table 1)                                                         56    N-(5,6-dihydro-7H-cyclopenta-                                                                      Pale yellow crystal                                      [d]pyrimidin-4-yl)-4-{3-[1-(6-                                                                     m.p. 200 to 201.5                                        methyl-2-pyridylmethyl)piperi-                                                                     °C.                                               din-4-yl]propanoyl}aniline                                                    (Compound II-238 in Table 1)                                            57    (E)-N-(5,6-dihydro-7H-cyclo-                                                                       Yellowish white                                          penta[d]pyrimidin-4-yl)-4-{3-                                                                      crystal                                                  [1-(2-thienylmethyl)piperidin-                                                                     m.p. 199 to 200° C.                               4-yl]propenoyl]aniline                                                        (Compound II-107 in Table 1)                                            58    N-(5,6-dihydro-7H-cyclopenta-                                                                      White crystal                                            [d]pyrimidin-4-yl)-4-{3-[1-(3,                                                                     m.p. 198.5 to 200                                        4-methylenedioxybenzyl)piperi-                                                                     °C.                                               din-4-yl]propanoyl}aniline                                                    (Compound II-231 in Table 1)                                            59    N-(5,6-dihydro-7H-cyclopenta-                                                                      Yellowish white                                          [d]pyrimidin-4-yl)-4-{3-[1-(3,                                                                     crystal                                                  4-ethylenedioxybenzyl)piperi-                                                                      m.p. 185 to 186° C.                               din-4-yl]propanoyl}aniline                                                    (Compound II-235 in Table 1)                                            60    N-(5,6-dihydro-7H-cyclopenta-                                                                      White crystal                                            [d]pyrimidin-4-yl)-4-{3-[1-(2,                                                                     m.p. 179 to 181° C.                               3-dimethoxybenzyl)piperidin-4-                                                yl]propanoyl}aniline (Compound                                                II-233 in Table 1)                                                      61    N-(6,6-dimethyl-5,6-dihydro-7H-                                                                    (as 1/2H.sub.2 O adduct)                                 cyclopenta[d]pyrimidin-4-yl)-4-                                                                    Pale yellow crystal                                      [3-benzylpiperidin-4-yl)-                                                                          m.p. 225 to 227° C.                               propanoyl]aniline.2HCl (2HCl salt                                             of Compound II-198 in Table 1)                                          62    N-(pyrimidin-4-yl)-4-[3-(1-ben-                                                                    Pale yellow crystal                                      zylpiperidin-4-yl)propanoyl]-                                                                      m.p. 149.5 to 151                                        aniline (Compound II-136 in                                                                        °C.                                               Table 1)                                                                63    N-(5-methylpyrimidin-4-yl)-4-                                                                      (1/2H.sub.2 O adduct)                                    [3-(1-benzylpiperidin-4-yl)-                                                                       White powder                                             propanoyl]aniline.2HCl (2HCl salt                                                                  m.p. 180 to 184° C.                               of Compound II-189 in Table 1)                                          64    N-(5,6-diethylpyrimidin-4-yl)-                                                                     White needle crystal                                     4-[3-(1-benzylpiperidin-4-yl)-                                                                     m.p. 137 to 139° C.                               propanoyl]aniline (Compound II-                                               223 in Table 1)                                                         65    N-(5-butyl-6-methylpyrimidin-4-                                                                    White powder                                             yl)-4-[3-(1-benzylpiperidin-4-                                                                     m.p. 149.5 to 151                                        yl)propanoyl]aniline (Compound                                                                     °C.                                               II-154 in Table 1)                                                      66    N-(5-ethoxycarbonylpyrimidin-4-                                                                    Pale yellow crystal                                      yl)-4-[3-(1-benzylpiperidin-4-                                                                     m.p. 117 to 118.5                                        yl)propanoyl]aniline (Compound                                                                     °C.                                               II-222 in Table 1)                                                      67    N-(6-ethoxypyrimidin-4-yl)-4-                                                                      Pale yellow crystal                                      [3-(1-benzylpiperidin-4-yl)-                                                                       m.p. 168 to 170° C.                               propanoyl]aniline (Compound II-                                               149 in Table 1)                                                         68    N-(6-chloro-5-methylpyrimidin-                                                                     (as 1/2H.sub.2 O adduct)                                 4-yl)-4-[3-(1-benzylpiperidin-                                                                     White needle crystal                                     4-yl)propanoyl]aniline                                                                             m.p. 175 to 177° C.                               (Compound II-190 in Table 1)                                            69    N-(5-chloropyrimidin-4-yl)-4-                                                                      Pale brown crystal                                       [3-(1-benzylpiperidin-4-yl)-                                                                       m.p. 142 to 144° C.                               propanoyl]aniline (Compound II-                                               229 in Table 1)                                                         70    N-(5-bromopyrimidin-4-yl)-4-[3-                                                                    Pale yellow crystal                                      (1-benzylpiperidin-4-yl)propan-                                                                    m.p. 151 to 153° C.                               oyl]aniline (Compound II-230 in                                               Table 1)                                                                71    N-(5-nitro-6-methoxypyrimidin-                                                                     Yellow crystal                                           4-yl)-4-[3-(1-benzylpiperidin-                                                                     m.p. 126 to 128° C.                               4-yl)propanoyl]aniline                                                        (Compound II-240 in Table 1)                                            72    N-(5-methylpyrimidin-4-yl)-4-                                                                      White crystal                                            {3-[1-(2-pyridylmethyl)piperi-                                                                     m.p. 142 to 143° C.                               din-4-yl)propanoyl]aniline                                                    (Compound II-248 in Table 1)                                            73    N-(5-amino-6-chloropyrimidin-4-                                                                    (as 1/4H.sub.2 O adduct)                                 yl)-4-[3-(1-benzylpiperidin-4-                                                                     Yellowish orange                                         yl)propanoyl]aniline (Compound                                                                     crystal                                                  II-241 in Table 1)   m.p. 163 to 165° C.                         74    N-(5,6-dihydro-7H-cyclopenta-                                                                      White powder                                             [d]pyrimidin-4-yl)-4-{3-[1-(4-                                                                     m.p. 200 to 202° C.                               nitrobenzyl)piperidin-4-yl]-                                                  propanoyl}aniline (Compound II-                                               74 in Table 1)                                                          75    N-(5,6-dihydro-7H-cyclopenta-                                                                      White powder                                             [d]pyrimidin-4-yl)-4-{3-[1-(3-                                                                     m.p. 184.5 to 186                                        nitrobenzyl)piperidin-4-yl]-                                                                       °C.                                               propanoyl}aniline (Compound II-                                               243 in Table 1)                                                         76    N-(5,6-dihydro-7H-cyclopenta-                                                                      Pale brown powder                                        [d]pyrimidin-4-yl)-4-{3-[1-(4-                                                                     m.p. 174 to 176.5                                        aminobenzyl)piperidin-4-yl]-                                                                       °C.                                               propanoyl}aniline (Compound II-                                               271 in Table 1)                                                         77    N-(5,6-dihydro-7H-cyclopenta-                                                                      (as 1/2H.sub.2 O adduct)                                 [d]pyrimidin-4-yl)-4-{3-[1-(3-                                                                     White needle crystal                                     aminobenzyl)piperidin-4-yl]-                                                                       m.p. 187 to 188° C.                               propanoyl}aniline (Compound II-                                               244 in Table 1)                                                         78    N-(5,6-dihydro-7H-cyclopenta-                                                                      White powder                                             [d]pyrimidin-4-yl)-4-{3-[1-(4-                                                                     NMR (δ, CD.sub.3 OD);                              hydroxybenzyl)piperidin-4-yl]-                                                                     1.20-1.49 (3H, m),                                       propanoyl}aniline (Compound II-                                                                    1.58-1.80 (4H, m),                                       44 in Table 1)       1.98-2.10 (2H, m),                                                            2.15-2.27 (2H, m),                                                            2.87-3.03 (8H, m),                                                            3.59 (2H, s), 6.86                                                            (2H, d, J=8.4Hz),                                                             7.29 (2H, d, J=8.4                                                            Hz), 7.90 (2H, d,                                                             J=8.8Hz), 7.98 (2H,                                                           d, J=8.8Hz), 8.51                                                             (1H, s)                                            ______________________________________                                    

EXAMPLES 79 TO 91

In the same manner as in Example 3, 25, 26, 27 or 31, the followingcompounds were obtained.

    ______________________________________                                        Exam-                      Characteristics.                                   ple   Compound             Physical properties                                ______________________________________                                        79    N-(5,6-dimethylpyrimidin-4-yl-                                                                     White crystal                                            4-[(1-benzylpiperidin-4-yl)-                                                                       m.p. 212 to 214° C.                               acetyl]aniline (Compound II-234                                               in Table 1)                                                             80    N-(5,6-dihydro-7H-cyclopenta-                                                                      (as 3/2H.sub.2 O adduct)                                 [d]pyrimidin-4-yl)-4-[(1-benz-                                                                     White crystal                                            ylpiperidin-4-yl)acetyl]-2-                                                                        m.p. 228 to 232° C.                               methoxyaniline.2HCl (2HCl salt                                                of Compound II-245 in Table 1)                                          81    N-(5,6,7,8-tetrahydroquinazo-                                                                      (as H.sub.2 O adduct)                                    lin-4-yl)-4-[(1-benzylpiperi-                                                                      White crystal                                            din-4-yl)acetyl]-2-methoxy-                                                                        m.p. 215 to 219° C.                               aniline.2HCl (2HCl salt of                                                    Compound II-246 in Table 1)                                             82    N-(5,6-dihydro-7H-cyclopenta-                                                                      Pale yellow crystal                                      [d]pyrimidin-4-yl)-4-[(1-benz-                                                                     m.p. 128 to 130° C.                               ylpiperidin-4-yl)acetyl]-2-                                                   chloroaniline (Compound II-247                                                in Table 1)                                                             83    N-(5,6-dihydro-7H-cyclopenta-                                                                      Yellow crystal                                           [d]pyrimidin-4-yl)-4-{[1-(4-                                                                       m.p. 195 to 197° C.                               fluorobenzyl)-4-piperidinyli-                                                                      (decomposed)                                             den]acetyl}aniline (Compound                                                  II-10 in Table 1)                                                       84    N-(5,6-dihydro-7H-cyclopenta-                                                                      White crystal                                            [d]pyrimidin-4-yl)-4-{[1-(4-                                                                       m.p. 191 to 193° C.                               fluorobenzyl)piperidin-4-yl]-                                                 acetyl}aniline (Compound II-7                                                 in Table 1)                                                             85    N-(5,6-dihydro-7H-cyclopenta-                                                                      White crystal                                            [d]pyrimidin-4-yl)-4-{[1-(2-                                                                       m.p. 196 to 197.5                                        pyridylmethyl)piperidi-4-yl]-                                                                      °C.                                               acetyl}aniline (Compound II-109                                               in Table 1)                                                             86    N-(5,6-dihydro-7H-cyclopenta-                                                                      Yellowish white                                          [d]pyrimidin-4-yl)-4-{[1-(2-                                                                       crystal                                                  methoxybenzyl)piperidin-4-yl]-                                                                     m.p. 168 to 170° C.                               acetyl}aniline (Compound II-37                                                in Table 1)                                                             87    N-(5,6-dihydro-7H-cyclopenta-                                                                      White crystal                                            [d]pyrimidin-4-yl)-4-{[1-(2-                                                                       m.p. 197 to 199° C.                               thienylmethyl)piperidin-4-yl]-                                                acetyl}aniline (Compund II-103                                                in Table 1)                                                             88    N-(5-methylpyrimidin-4-yl)-4-                                                                      White crystal                                            {[1-(2-thienylmethyl)piperidin-                                                                    m.p. 209 to 211° C.                               4-yl]acetyl}aniline (Compound                                                 II-258 in Table 1)                                                      89    N-(5-methylpyrimidin-4-yl)-4-                                                                      White crystal                                            [(1-phenethylpiperidin-4-yl)-                                                                      m.p. 193 to 194° C.                               acetyl]aniline (Compound II-301                                               in Table 1)                                                             90    N-(5-methylpyrimidin-4-yl)-4-                                                                      White crystal                                            [(1-diphenylmethylpiperidin-4-                                                                     m.p. 195.5 to 197                                        yl)acetyl]aniline (Compound II-                                                                    °C.                                               302 in Table 1)                                                         91    N-(5,6-dihydro-7H-cyclopenta-                                                                      White crystal                                            [d]pyrimidin-4-yl)-4-{[1-(2-                                                                       m.p. 207 to 209° C.                               furylmethyl)piperidin-4-yl]-                                                  acetyl}aniline (Compund II-269                                                in Table 1)                                                             92    N-(5-methylpyrimidin-4-yl)-4-                                                                      Yellowish white                                          {[1-(3-phenylpropyl)piperidin-                                                                     crystal                                                  4-yl]acetyl}aniline (Compound                                                                      m.p. 167.5 to 169                                        II-317 in Table 1)   °C.                                         93    N-(5-ethylpyrimidin-4-yl)-4-                                                                       White crystal                                            [(1-benzylpiperidin-4-yl)-                                                                         m.p. 169 to 171° C.                               acetyl]aniline (Compound II-252                                               in Table 1)                                                             94    N-(5-propylpyrimidin-4-yl)-4-                                                                      Yellow crystal                                           [(1-benzylpiperidin-4-yl)-                                                                         m.p. 140.5 to 141.5                                      acetyl]aniline (Compound II-253                                                                    °C.                                               in Table 1)                                                             95    N-(5-methylpyrimidin-4-yl)-4-                                                                      White crystal                                            {[1-(3-thienylmethyl)piperidin-                                                                    m.p. 212 to 214° C.                               4-yl]acetyl}aniline (Compound                                                 II-259 in Table 1)                                                      96    N-(5,6-dihydro-7H-cyclopenta-                                                                      Yellowish white                                          [d]pyrimidin-4-yl)-4-{[1-(3-                                                                       crystal                                                  thienylmethyl)piperidin-4-yl]-                                                                     m.p. 193 to 195° C.                               acetyl}aniline (Compound II-267                                               in Table 1)                                                             97    N-(5-methylpyrimidin-4-yl)-4-                                                                      Pale brown crystal                                       [(1-benzylpiperidin-4-yl)-                                                                         m.p. 168 to 170° C.                               acetyl]-3-methoxyaniline                                                      (Compound II-266 in Table 1)                                            ______________________________________                                    

Reference Example 1 4-[3-(1-benzylpiperidin-4-yl)propenoyl]nitrobenzene

Under ice cooling, 0.40 g of 64% sodium hydride was added to 3.03 g ofdiethyl (4-nitrobenzoylmethyl)phosphonate dissolved in 30 ml oftetrahydrofuran. After about 10 minutes, 4.07 g of4-formyl-1-benzylpiperidine was added to the mixture. The mixture wasstirred under ice cooling for 30 minutes and then stirred at roomtemperature for about 16 hours. After completion of the reaction, waterwas added to the reaction mixture, and the mixture was extracted withethyl acetate. The extract was dried over anhydrous sodium sulfate, andthe solvent was removed under reduced pressure. The obtained residue wasapplied to silica gel column chromatography to obtain 1.99 g of thetitle compound as pale yellow crystal.

Mass; m/z=350 (M⁺)

NMR (δ, CDCl₃); 1.47 to 1.70 (2H, m), 1.70 to 1.87 (2H, m), 1.97 to 2.16(2H, m), 2.16 to 2.40 (1H, m), 2.86 to 3.02 (2H, m), 3.53 (2H, m), 6.82(1H, dd, J=15.6 Hz, J=-1 Hz), 7.09 (1H, dd, J=15.6 Hz, J=6.4 Hz), 7.21to 7.37 (5H, m), 8.03 (2H, d, J=8.8 Hz), 8.32 (2H, d, J=8.8 Hz)

Reference Example 2 (E)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]aniline

1.27 g of (E)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]nitrobenzene wasadded to a mixed solution of 10 ml of acetic acid and 2 ml ofhydrochloric acid, and then 1.38 g of stannous chloride was addedthereto under ice cooling. The mixture was stirred for 24 hours. Duringthe reaction, 0.69 g of stannous chloride was further added twice. Aftercompletion of the reaction, the reaction mixture was condensed underreduced pressure to obtain 5.50 g of a crude product of the titlecompound. This was used without purification for the next reaction.

Mass; m/z=320 (M⁺)

TLC Rf value; 0.42 (silica gel produced by Merck Co.; 60F₂₅₄, solvent;chloroform/methanol=9/1)

Reference Example 34-[3-(1-t-butoxycarbonylpiperidin-4-yl)propenoyl]nitrobenzene

0.28 g of lithium chloride, 0.85 g of diisopropylethylamine and 2.13 gof 4-formyl-l-t-butoxycarbonylpiperidine were added to 2.0 g of diethyl(4-nitrobenzoylmethyl)phosphonate dissolved in 20 ml of acetonitrile,and the mixture was stirred at room temperature for about 3 days. Then,water was added to the reaction mixture, and the mixture was extractedwith toluene. The extract was dried over anhydrous sodium sulfate andcondensed. The obtained residue was applied to silica gel columnchromatography to obtain 1.76 g of the title compound as pale yellowcrystal.

Mass (CI); m/z=261 (M⁺ -99)

NMR (δ, CDCl₃); 1.37 to 1.53 (2H, m), 1.47 (9H, s), 1.77 to 1.86 (2H,m), 2.40 to 2.52 (2H, m), 2.74 to 2.87 (2H, m), 4.08 to 4.28 (2H, m),6.85 (1H, dd, J=1.5 Hz, 15.6 Hz), 7.06 (1H, dd, J=6.4 Hz, 15.1 Hz), 8.05(2H, d, J=8.8 Hz), 8.32 (2H, d, J=8.8 Hz)

Reference Example 4 (E)-4-[3-(piperidin-4-yl)propenoyl]nitrobenzene

3 ml of trifluoroacetic acid was added to 2.52 g of(E)-4-[3-(1-t-butoxycarbonylpiperidin-4-yl)propenoyl]nitrobenzenedissolved in 20 ml of methylene chloride, and the mixture was stirred atroom temperature for 3 hours. Subsequently, 7 ml of trifluoroacetic acidwas further added to the mixture, and the mixture was stirred for 3hours. Then, the solvent was removed by distillation, and a saturatedsodium hydrogen carbonate solution was added to the residue. After themixture was extracted with ethyl acetate, the extract was dried overanhydrous sodium sulfate and condensed. The obtained solid was washedwith methylene chloride to obtain 0.7 g of the title compound as paleyellow powder.

Mass (CI); m/z=261 (M⁺ +1)

NMR (δ, CDCl₃ -DMSO-d₆); 1.80 to 2.12 (4H, m), 2.30 to 2.70 (1H, m),2.89 to 3.08 (2H, m), 3.44 to 3.68 (2H, m), 6.90 (1H, d, J=15 to 16 Hz),7.04 (1H, dd, J=15 to 16 Hz, J=6 to 7 Hz), 8.06 (2H, d, J=8 to 9 Hz),8.32 (2H, d, J=8 to 9 Hz)

Reference Example 5(E)-4-{3-[1-(3-fluorobenzyl)piperidin-4-yl]propenoyl}nitrobenzene

1.11 g of 3-fluorobenzylbromide and 2.53 g of potassium carbonate wereadded to 3.0 g of (E)-4-[3-(piperidin-4-yl)propenoyl]nitrobenzenedissolved in 30 ml of dimethylformamide at room temperature, and themixture was stirred for 2 hours. After completion of the reaction, waterwas added to the reaction mixture, and the mixture was extracted withethyl acetate. The extract was dried over anhydrous sodium sulfate, andthe solvent was removed under reduced pressure. The obtained residue wasapplied to silica gel column chromatography to obtain 1.06 g of thetitle compound as pale yellow crystal.

Mass (CI); m/z=369 (M⁺ +1)

NMR (δ, CDCl₃); 1.46 to 1.88 (4H, m), 2.00 to 2.12 (2H, m), 2.18 to 2.40(1H, m), 2.84 to 3.50 (2H, m), 3.51 (2H, s), 6.82 (1H, dd, J=-1 Hz, 15.6Hz), 6.88 to 6.99 (1H, m), 7.03 to 7.14 (3H, m), 7.20 to 7.34 (1H, m),8.04 (2H, d, J=8.8 Hz), 8.31 (2H, d, J=8.8 Hz)

In the same manner as in Reference example 5, the following compoundswere obtained.

Reference Example 6(E)-4-{3-[1-(4-fluorobenzyl)piperidin-4-yl]propenoyl}-nitrobenzene

Orange powder

Mass (CI); m/z=369 (M⁺ +1)

NMR (δ, CDCl₃); 1.45 to 1.88 (4H, m), 1.92 to 2.16 (2H, m), 2.16 to 2.40(1H, m), 2.85 to 3.00 (2H, m), 3.47 (2H, s), 6.81 (1H, dd, J=-1 Hz, 15.6Hz), 6.95 to 7.05 (2H, m), 7.07 (1H, dd, J=6.4 Hz, J=15.6 Hz), 7.24 to7.31 (2H, m), 8.03 (2H, d, J=8.8 Hz), 8.31 (2H, d, J=8.8 Hz)

Reference Example 7(E)-4-(3-[1-(4-methoxybenzyl)piperidin-4-yl]propenoyl)nitrobenzene

Brown oily product

Mass; m/z=380 (M⁺)

NMR (δ, CDCl₃); 1.46 to 1.84 (4H, m), 1.97 to 2.10 (2H, m), 2.20 to 2.35(1H, m), 2.91 to 2.99 (2H, m), 3.46 (2H, s), 3.82 (3H, s), 6.88 to 6.92(3H, m), 7.10 (1H, dd, J=6 to 7 Hz, 15 to 16 Hz), 7.22 to 7.35 (2H, m),8.03 (2H, d, J=8 to 9 Hz), 8.32 (2H, d, J=8 to 9 Hz)

Reference Example 8(E)-4-(3-[1-(4-picolyl)piperidin-4-yl]propenoyl)nitrobenzene

Brown crystal

Mass; m/z=351 (M⁺)

NMR (δ, CDCl₃); 1.55 to 1.66 (2H, m), 1.78 to 1.85 (2H, m), 1.85 to 2.14(2H, m), 2.25 to 2.37 (1H, m), 2.87 to 2.97 (2H, m), 3.53 (2H, s), 6.83(1H, d, J=15.6 Hz), 7.08 (1H, dd, J=6.8 Hz, J=15.6 Hz), 7.28 (2H, d,J=5.9 Hz), 8.05 (2H, d, J=8.8 Hz), 8.32 (2H, d, J=8.8 Hz), 8.55 (2H, d,J=5.9 Hz)

Reference Example 94-chloro-7-fluoro-5,6-dihydro-7H-cyclopenta[d]pyrimidine

(1) 5.54 g of lithium hydroxide·hydrate was added to 24.2 g of7-acetoxy-4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine dissolved in150 ml of tetrahydrofuran, and the mixture was stirred at roomtemperature for about 20 hours. After the reaction, water was added tothe reaction mixture, and then the mixture was extracted withchloroform. The extract was dried over anhydrous sodium sulfate and thencondensed. The obtained residue was applied to silica gel columnchromatography to obtain 10.5 g of4-chloro-7-hydroxy-5,6-dihydro-7H-cyclopenta[d]pyrimidine.

Mass; m/z=170

NMR (δ, CDCl₃); 2.00 to 2.23 (1H, m), 2.52 to 2.73 (1H, m), 2.79 to 3.02(1H, m), 3.02 to 3.24 (1H, m), 5.20 (1H, br), 5.30 (1H, t, J=8.0 Hz),8.90 (1H, s)

(2) Under ice cooling, 3.9 ml of diethylaminosulfite trifluoride (DAST)was added dropwise to 5.00 g of4-chloro-7-hydroxy-5,6-dihydro-7H-cyclopenta[d]pyrimidine obtained abovedissolved in 40 ml of chloroform, and the mixture was stirred at thesame temperature for 10 minutes. After the solvent was removed underreduced pressure, water was added to the mixture, and the mixture wasextracted with ethyl acetate. The extract was dried over anhydroussodium sulfate and condensed. The obtained residue was applied to silicagel column chromatography to obtain 3.09 g of the title compound as ayellow oily product.

Mass; m/z=172 (M⁺)

NMR (δ, CDCl₃); 2.23 to 2.77 (2H, m), 2.87 to 3.40 (2H, m), 5.78 to 5.89and 6.05 to 6.18 (total 1H, each m), 9.01 (1H, s)

Reference Example 10 4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline

2.00 g of (E)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]nitrobenzene wasadded to a mixed solvent of 30 ml of ethanol and 5 ml of acetic acid,and then 0.20 g of platinum oxide was added thereto. Thereafter, themixture was stirred in a hydrogen stream at room temperature for 7.5hours. After the reaction, the catalyst was removed by filtration, andthe filtrate was condensed under reduced pressure. The obtained residuewas applied to silica gel column chromatography to obtain 0.69 g of thetitle compound as pale yellow crystal.

Mass; m/z=322 (M⁺)

NMR (δ, CDCl₃); 1.32 to 1.54 (3H, m), 1.63 to 1.78 (4H, m), 2.14 to 2.25(2H, m), 2.86 (2H, t, J=7.3 Hz), 3.09 to 3.18 (2H, m), 3.77 (2H, s),6.63 (2H, d, J=8.8 Hz), 7.28 to 7.37 (5H, m), 7.78 (2H, d, J=8.8 Hz)

Reference Example 11 (E)-4-[3-(1-acetylpiperidin-4-yl)propenoyl]nitrobenzene

In the same manner as in Reference example 3 except for using4-formyl-l-acetylpiperidine in place of4-formyl-t-butoxycarbonylpiperidine, the reaction was carried out toobtain the title compound as yellowish orange solid.

Mass; m/z=302 (M⁺)

NMR (δ, CDCl₃); 1.36 to 1.57 (2H, m), 1.83 to 1.99 (2H, m), 2.12 (3H,s), 2.48 to 2.75 (2H, m), 3.10 to 3.25 (1H, m), 3.85 to 3.96 (1H, m),4.63 to 4.75 (1H, m), 6.86 (1H, d, J=15.9 Hz), 7.06 (1H, dd, J=15.8 Hz,6.7 Hz), 8.06 (2H, d, J=9.2 Hz), 8.32 (2H, d, J=9.2 Hz)

Reference Example 12 4-[3-(1-acetylpiperidin-4-yl) propanoyl]aniline

To 6.74 g of (E)-4-[3-(1-acetylpiperidin-4-yl)propenoyl]nitrobenzenewere added 300 ml of methanol and 0.30 g of platinum oxide, and under ahydrogen stream, the mixture was stirred at room temperature for 3hours. Then, the solid was removed by filtration, the solvent wasremoved by distillation under reduced pressure, and the obtained residuewas applied to silica gel column chromatography to obtain 4.81 g of thetitle compound as brownish white powder.

Mass; m/z=274 (M⁺)

NMR (δ, CDCl₃); 1.02 to 1.25 (2H, m), 1.46 to 1.86 (5H, m), 2.08 (3H,s), 2.43 to 2.61 (1H, m), 2.90 (2H, t, J=7.3 Hz), 2.95 to 3.09 (1H, m),3.70 to 3.86 (1H, m), 4.27(2H, s, br), 4.52 to 4.64 (1H, m), 6.65 (2H,d, J=8.6 Hz), 7.80 (2H, d, J=8.6 Hz)

Reference Example 13N-acetyl-4-[(1-benzyl-4-hydroxypiperidin-4-yl)acetyl]aniline

A mixed solution comprising 140 ml of a tetrahydrofuran solutioncontaining 10.00 g of 4-acetylaminoacetophenone and 10 ml ofhexamethylphosphoric acid triamide (HMPA) was cooled to -60° C. under anargon stream, and then 83 ml of a tetrahydrofuran solution containing1.5M of lithium diisopropylamide was added dropwise to the mixture.After completion of the dropwise addition, the mixture was stirred at-35° to -30° C. for 20 minutes and cooled again to -60° C. To themixture was added dropwise 10.68 g of 1-benzyl-4-piperidone, and thetemperature of the resulting mixture was gradually raised to roomtemperature. The reaction mixture was quenched to a saturated ammoniumchloride aqueous solution, and 3.62 g of the precipitated title compoundwas collected by filtration. The filtrate was further extracted withethyl acetate and condensed, and then the condensate was applied tosilica gel column chromatography to obtain 8.28 g of the title compound.

White crystal

Mass (CI); m/z=349 (M⁺ +1-H₂ O)

NMR (δ, CDCl₃); 1.67 to 1.89 (4H, m), 2.22 (3H, s), 2.50 to 2.77 (4H,m), 3.05 (2H, s), 3.62 (2H, s), 4.14 (1H, s), 7.21 to 7.45 (5H, m), 7.66(2H, d, J=9.2 Hz), 7.87 (2H, d, J=9.2 Hz), 8.07 (1H, s, br)

Reference Example 14N-acetyl-4-[(1-benzyl-4-piperidinyliden)acetyl]aniline andN-acetyl-4-[(1-benzyl-1,2,5,6-tetrahydropyridin-4-yl)acetyl]aniline

To a chloroform solution containing 11.90 g ofN-acetyl-4-[(1-benzyl-4-hydroxypiperidin-4-yl)acetyl]aniline was added15 ml of pyridine under ice cooling, and then 3.8 ml of thionyl chloridewas added dropwise thereto. After completion of the dropwise addition,the mixture was stirred at room temperature for about 6 hours. Aftercompletion of the reaction, ice-water was added and then a 1N sodiumhydroxide aqueous solution was added to the mixture to make it weakalkaline, then the mixture was extracted with chloroform. The extractwas dried over anhydrous sodium sulfate and then condensed. The residueobtained was applied to silica gel column chromatography to obtain 7.11g of the mixture of the title compounds.

Brown liquid

Mass (CI); m/z=349 (M⁺ +1)

NMR (δ, CDCl₃); 2.20 (3H, s), 2.37 to 2.63, 2.85 to 3.02 and 3.60 (total8H, each m), 3.53 and 3.56 (total 2H, each s), 5.52 and 6.62 (total 1H,m and s, respectively), 7.18 to 7.39 (5H, m), 7.62 (2H, d, J=8.6 Hz),7.85 to 8.05 (3H, m)

Reference Example 15 N-acetyl-4-[(1-benzylpiperidin-4-yl)acetyl]aniline

In a mixed solution of 80 ml of ethanol and 30 ml of toluene wasdissolved 7.10 g of the mixture ofN-acetyl-4[(1-benzyl-4-piperidinyliden)acetyl]aniline andN-acetyl-4[(1-benzyl-1,2,5,6-tetrahydropyridin-4-yl)acetyl]anilineobtained in Reference example 14, and then 0.10 g of platinum oxide wasadded thereto. The mixture was stirred under a hydrogen stream for 5.5hours. After the reaction, the catalyst was removed by filtration andcondensed under reduced pressure. The residue obtained was applied tosilica gel column chromatography to obtain 5.54 g of the title compound.

Pale yellow crystal

Mass (CI); m/z=351 (M⁺ +1)

NMR (δ, CDCl₃); 1.25 to 1.44 (2H, m), 1.63 to 1.77 (2H, m), 1.88 to 2.07(3H, m), 2.19 (3H, s), 2.76 to 2.92 (4H, m), 3.48 (2H, s), 7.18 to 7.38(5H, m), 7.62 (2H, d, J=9.2 Hz), 7.89 (2H, d, J=9.2 Hz), 8.13 (1H, s,br)

Reference example 16 4-[(1-benzylpiperidin-4-yl)acetyl]aniline·2HCl salt

5.54 g of N-acetyl-4-[(1-benzylpiperidin-4-yl)acetyl]aniline was addedto a mixed solution of 15 ml of ethanol and 20 ml of conc. hydrochloricacid, and then the mixture was heated under reflux for 4.5 hours. Afterthe reaction, the reaction mixture was condensed under reduced pressure,and the obtained solid was washed with ethanol to obtain 6.20 g of thetitle compound.

Pale brown crystal

Mass (CI); m/z=309 (M⁺ +1)

NMR (δ, CDCl₃ -DMSO-d₆); 1.68 to 1.97 (4H, m), 2.07 to 2.28 (1H, m),2.82 to 3.10 (4H, m), 3.29 to 3.43 (2H, m), 4.27 (2H, d, J=5.5 Hz), 7.18(2H, d, J=8.7 Hz), 7.31 to 7.51 (3H, m), 7.58 to 7.76 (2H, m), 7.87 (2H,d, J=8.7 Hz)

Reference Example 17N-t-butoxycarbonyl-4-[(1-benzyl-4-hydroxypiperidin-4-yl)acetyl]aniline

30 ml of tetrahydrofuran was added to 2.00 g ofN-t-butoxycarbonyl-4-acetylaniline, and 8.8 ml of a 1.7M t-butyllithium·pentane solution was added thereto under an argon stream at -78°C. Then, 1.41 g of 1-benzyl-4-piperidone was dissolved in 20 ml oftetrahydrofuran, and the solution was added dropwise. After stirring for2 hours, a saturated ammonium chloride aqueous solution was added to thereaction mixture, and the mixture was extracted with ethyl acetate anddried over anhydrous sodium sulfate. The solvent was removed bydistillation under reduced pressure, and the obtained residue wasapplied to silica gel column chromatography to obtain 2.07 g of thetitle compound as white powder.

Mass (CI); m/z=307 (M⁺ -118)

NMR (δ, CDCl₃); 1.53 (9H, s), 1.60 to 1.75 (2H, m), 1.75 to 1.83 (2H,m), 2.43 to 2.53 (2H, m), 2.56 to 2.65 (2H, m), 3.06 (2H, s), 3.54 (2H,s), 4.10 (1H, s, br), 6.74 (1H, s, br), 7.23 to 7.35 (5H, m), 7.45 (2H,d, J=8.8 Hz), 7.89 (2H, d, J=8.8 Hz)

Reference Example 184-[(1-benzyl-4-hydroxypiperidin-4-yl)acetyl]aniline·trifluoroacetate

30 ml of chloroform was added to 2.07 g ofN-t-butoxy-carbonyl-4-[(1-benzyl-4-hydroxypiperidin-4-yl)acetyl]aniline,trifluoroacetic acid was added thereto three times in a total amount of8 ml, and the mixture was stirred at room temperature. Thereafter, thesolvent was removed by distillation under reduced pressure, and theobtained residue was applied to silica gel column chromatography toobtain 1.14 g of the title compound as reddish white powder.

Mass (CI); m/z=325 (M⁺ +1)

NMR (δ, CDCl₃); 1.88 to 1.96 (2H, m), 2.01 to 2.16 (2H, m), 3.03 (2H,s), 3.13 to 3.36 (4H, m), 4.19 (2H, s), 5.01 (2H, br), 6.63 (2H, d,J=8.8 Hz), 7.38 to 7.55 (5H, m), 7.73 (2H, d, J=8.8 Hz), 12.07 (1H, br)

Reference Example 19 (a)N-t-butoxycarbonyl-4-[(1-benzyl-4-piperidinyliden)acetyl]aniline and (b)N-t-butoxycarbonyl-4-[(1-benzyl-1,2,5,6-tetrahydropyridin-4-yl)acetyl]aniline

100 ml of chloroform was added to 14.9 g ofN-t-butoxycarbonyl-4-[2-(1-benzyl-4-hydroxypiperidin-4-yl)acetyl]aniline.After 3.1 ml of thionyl chloride was added to the mixture under icecooling, 11.8 ml of triethylamine was added dropwise thereto. After themixture was stirred at room temperature for 1 hour, water was added tothe reaction mixture, and the mixture was extracted with chloroform. Theextract was dried over anhydrous sodium sulfate, and the solvent wasremoved by distillation under reduced pressure. The obtained residue wasapplied to silica gel column chromatography to obtain the titlecompounds, respectively.

Compound of (a)

White powder

Mass (CI); m/z=407 (M⁺ +1)

NMR (δ, CDCl₃); 1.57 (9H, s), 2.38 to 2.49 (2H, m), 2.49 to 2.67 (4H,m), 2.86 to 3.00 (2H, m), 3.56 (2H, s), 6.61 (1H, s), 6.66 (1H, s), 7.23to 7.39 (5H, m), 7.44 (2H, d, J=8.5 Hz), 7.90 (2H, d, J=8.5 Hz)

Compound of (b)

White powder

Mass (CI); m/z=407 (M⁺ +1)

NMR (δ, CDCl₃); 1.52 (9H, s), 2.11 to 2.22 (2H, m), 2.22 to 2.54 (2H,m), 2.95 to 3.04 (2H, m), 3.57 (4H, s), 5.50 to 5.56 (1H, m), 6.76 (1H,s, br), 7.19 to 7.39 (5H, m), 7.43 (2H, d, J=8.8 Hz), 7.92 (2H, d, J=8.8Hz)

Reference Example 20 4-[(1-benzyl-4-piperidinylidene)acetyl]aniline

4.12 g ofN-t-butoxycarbonyl-4-[(1-benzyl-4-piperidinyliden)acetyl]aniline wasadded to 50 ml of chloroform, and then 10 ml of trifluoroacetic acid wasadded thereto. The mixture was stirred at room temperature for 4 hours.After the reaction, the reaction mixture was condensed under reducedpressure, and the residue was dissolved in chloroform. Then, thesolution was neutralized by adding a 28% sodium methylate·methanolsolution thereto. The residue obtained by condensation under reducedpressure was applied to silica gel column chromatography to obtain 2.33g of the title compound as bluish green powder.

Mass; m/z=306 (M⁺)

NMR (δ, CDCl₃); 2.29 to 2.69 (2H, m), 2.69 to 3.05 (2H, m), 3.31 to 3.86(4H, m), 4.22 (2H, s), 6.64 (2H, d, J=8.6 Hz), 6.71 (1H, s), 7.73 (2H,d, J=9.2 Hz)

Reference Example 21N-t-butoxycarbonyl-4-[(1-acetyl-4-hydroxypiperidin-4-yl)acetyl]aniline

In the same manner as in Reference example 17 except for using1-acetyl-4-piperidone in place of 1-benzyl-4-piperidone, the reactionwas carried out to obtain the title compound as white solid.

Mass (SIMS); 377 (M⁺ +1)

NMR (δ, CDCl₃); 1.37 to 1.62 (2H, m), 1.53 (9H, s ), 1.75 to 1.95 (2H,m), 2.10 (3H, s), 3.06 (2H, s), 3.47 to 3.67 (2H, m), 4.32 to 4.47 (2H,m), 7.07 (1H, s, br), 7.50 (2H, d, J=8.8 Hz ), 7.88 (2H, d, J=8.8 Hz )

Reference Example 22N-t-butoxycarbonyl-4-[(1-acetyl-4-piperidinyliden)acetyl]aniline andN-t-butoxycarbonyl-4-[(1-acetyl-1,2,5,6-tetrahydropyridin-4-yl)acetyl]aniline

In the same manner as in Reference example 14, the reaction was carriedout by using the compound obtained in Reference example 21 to obtain themixture of the title compounds.

Yellowish white powder

Mass (CI); m/z=359 (M⁺ +1)

NMR (δ, CDCl₃); 1.53 (9H, s), 2.12 and 2.16 (total 3H, each s), 1.98 to2.30, 2.38 to 2.57, 2.85 to 3.01, 3.38 to 3.82 and 3.82 to 4.13 (total8H, each m), 5.45 to 5.64 and 7.01 (total 1H, m and s, respectively),6.75 and 7.01 (total 1H, s, respectively), 7.47 (2H, d, J=8.8 Hz), 7.91(2H, d, J=8.8 Hz)

Reference Example 23N-t-butoxycarbonyl-4-[(1-acetylpiperidin-4-yl)acetyl]aniline

In the same manner as in Reference example 15, the reaction was carriedout by using the mixture obtained in Reference example 22 to obtain thetitle compound as white powder.

Mass (CI); m/z=261 (M⁺ -99)

NMR (δ, CDCl₃); 1.11 to 1.32 (2H, m), 1.53 (9H, s), 1.72 to 1.90 (2H,m), 2.08 (3H, s), 2.15 to 2.34 (1H, m), 2.53 to 2.66 (1H, m), 2.82 to2.90 (2H, m), 3.02 to 3.17 (1H, m), 3.73 to 3.85 (1H, m), 4.57 to 4.68(1H, m), 6.79 (1H, s, br), 7.46 (2H, d, J=8.8 Hz), 7.90 (2H, d, J=8.8Hz)

Reference Example 24 4-[(1-acetylpiperidin-4-yl) acetyl]aniline

50 ml of chloroform was added to 6.90 g ofN-t-butoxy-carbonyl-[4-(1-acetylpiperidin-4-yl)acetyl]aniline, andtrifluoroacetic acid was added to the mixture at room temperature untilno foaming occurred. The solvent was removed by distillation underreduced pressure, water was added to the residue, and the mixture wasneutralized with sodium hydrogen carbonate and then extracted withchloroform. After the extract was dried over anhydrous sodium sulfate,the solvent was removed by distillation under reduced pressure. Theobtained residue was applied to silica gel column chromatography toobtain 3.56 g of the title compound as yellow solid.

Mass (CI); m/z=261 (M⁺ +1)

NMR (δ, CDCl₃); 1.10 to 1.30 (2H, m), 1.68 to 1.91 (2H, m), 2.08 (3H,s), 2.12 to 2.34 (1H, m), 2.48 to 2.68 (1H, m), 2.68 to 2.93 (2H, m),3.00 to 3.17 (1H, m), 3.72 to 3.85 (1H, m), 4.54 (1H, m), 6.66 (2H, d,J=8.8 Hz), 7.80 (2H, d, J=8.8 Hz)

Reference Example 25N-t-butoxycarbonyl-4-[4-(1-benzylpiperidin-4-yl)-3-hydroxybutanoyl]aniline

50 ml of tetrahydrofuran was added to 3.80 g ofN-t-butoxycarbonyl-4-acetylaniline, and 19.0 ml of a 1.7M t-butyllithium·pentane solution was added dropwise thereto under an argonstream at -78° C. Subsequently, a solution of 3.50 g of(1-benzylpiperidin-4-yl)acetaldehyde dissolved in 10 ml oftetrahydrofuran was added to the mixture, and the resulting mixture wasstirred until its temperature was returned to room temperature. Then, asaturated ammonium chloride aqueous solution was added to the reactionmixture, the mixture was extracted with ethyl acetate, and the extractwas dried over anhydrous sodium sulfate. Then, the solvent was removedby distillation under reduced pressure, and the obtained residue wasapplied to silica gel column chromatography to obtain 4.57 g of thetitle compound as white powder.

Mass (CI); m/z=453 (M⁺ +1)

NMR (δ, CDCl₃); 1.15 to 1.42 (4H, m), 1.42 to 1.72 (4H, m), 1.53 (9H,s), 1.72 to 1.86 (1H, m), 1.86 to 2.08 (2H, m), 2.84 to 2.95 (2H, m),3.50 (2H, s), 4.23 to 4.38 (1H, m), 6.86 (1H, s, br), 7.13 to 7.40 (5H,m), 7.45 (2H, d, J=8.8 Hz), 7.89 (2H, d, J=8.8 Hz)

Reference Example 264-[4-(1-benzylpiperidin-4-yl)-3-hydroxybutanoyl]aniline·trifluoroacetate

50 ml of dichloromethane was added to 4.55 g ofN-t-butoxycarbonyl-4-[4-(1-benzylpiperidin-4-yl)-3-hydroxybutanoyl]aniline,and trifluoroacetic acid was added to the mixture at room temperatureuntil no foaming occurred. Then, the solvent was removed by distillationunder reduced pressure, and the obtained residue was applied to silicagel column chromatography to obtain 1.21 g of the title compound aswhite powder.

Mass (CI); m/z=353 (M⁺ +1)

NMR (δ, CDCl₃); 1.22 to 2.08 (7H, m), 2.62 to 2.84 (2H, m), 2.94 (2H, d,J=5.9 Hz), 3.42 to 3.62 (2H, m), 4.20 (3H, m, br), 6.63 (2H, d, J=8.8Hz), 7.36 to 7.55 (5H, m), 7.73 (2H, d, J=8.8 Hz)

Reference Examples 27 TO 42

In the same manner as in Reference example 5, the following compoundswere obtained.

    __________________________________________________________________________    Refer-                                                                        ence                                                                          example                                                                            Compound Mass                                                            No.  (characteristics)                                                                      (m/z)                                                                              NMR (δ, CDCl.sub.3)                                  __________________________________________________________________________    27   (E)-4-{3-[1-(2-                                                                        368  1.54 to 1.67 (2H, m), 1.77 to 1.86                              fluorobenzyl)-                                                                         (M.sup.+)                                                                          (2H, m), 2.08 to 2.18 (2H, m),                                  piperidin-4-  2.22 to 2.37 (1H, m), 2.92 to 3.01                              yl]propenoyl}-                                                                              (2H, m), 3.62 (2H, s), 6.82 (1H,                                nitrobenzene  d, J=15.6Hz), 7.00 to 7.17 (3H,                                 (brown liquid)                                                                              m), 7.21 to 7.30 (1H, m), 7.35 to                                             7.43 (1H, m), 8.03 (2H, d, J=                                                 8.8Hz), 8.31 (2H, d, J=8.8Hz)                              28   (E)-4-{3-[1-(3-                                                                        384  1.46 to 1.71 (2H, m), 1.75 to 1.89                              chlorobenzyl)-                                                                         (M.sup.+)                                                                          (2H, m), 2.00 to 2.19 (2H, m),                                  piperidin-4-  2.22 to 2.39 (1H, m), 2.85 to 3.04                              yl]propenoyl}-                                                                              (2H, m), 3.52 (2H, s), 6.83 (1H,                                nitrobenzene  d, J=15Hz), 7.09 (1H, dd, J=15Hz,                               (brown crystal)                                                                             6Hz), 7.15 to 7.41 (4H, m), 8.04                                              (2H, d, J=9Hz), 8.32 (2H, d, J=                                               9Hz)                                                       29   (E)-4-{3-[1-(3-                                                                        381  1.53 to 1.67 (2H, m), 1.75 to 1.85                              methoxybenzyl)-                                                                        (CI) (2H, m), 2.01 to 2.13 (2H, m),                                  piperidin-4-                                                                           (M.sup.+ +1)                                                                       2.24 to 2.37 (1H, m), 2.93 to 3.01                              yl]propenoyl}-                                                                              (2H, m), 3.51 (2H, s), 3.82 (3H,                                nitrobenzene  s), 6.82 (1H, d, J=15.6Hz), 6.80                                (yellowish    to 6.84 (1H, m), 6.86 to 6.95 (1H,                              brown crystal)                                                                              m), 7.08 (1H, dd, J=15.6Hz,                                                   8.7Hz), 7.22 to 7.28 (1H, m), 8.03                                            (2H, d, J=8.8Hz), 8.31 (2H, d,                                                J=8.8Hz)                                                   30   (E)-4-{3-[1-(2-                                                                        380  1.52 to 1.70 (2H, m), 1.70 to 1.85                              methoxybenzyl)-                                                                        (M.sup.+)                                                                          (2H, m), 2.05 to 2.20 (2H, m),                                  piperidin-4-  2.20 to 2.38 (1H, m), 2.94 to 3.06                              yl]propenoyl}-                                                                              (2H, m), 3.59 (2H, s), 3.82 (3H,                                nitrobenzene  s), 6.81 (1H, d, J=15.3Hz), 6.84                                (pale yellow  to 6.99 (2H, m), 7.08 (1H, dd, J=                               crystal)      15.3 Hz, 6.7Hz), 7.19 to 7.29 (1H,                                            m), 7.35 (1H, d, J=7.3Hz), 8.03                                               (2H, d, J=8.5Hz), 8.31 (2H, d,                                                J=8.5Hz)                                                   31   (E)-4-{3-[1-(3-                                                                        364  1.47 to 1.71 (2H, m), 1.71 to 1.89                              methylbenzyl)-                                                                         (M.sup.+)                                                                          (2H, m), 1.96 to 2.13 (2H, m),                                  piperidin-4-  2.21 to 2.40 (1H, m), 2.35 (3H,                                 yl]propenoyl}-                                                                              s), 2.88 to 3.03 (2H, m), 3.49                                  nitrobenzene  (2H, s), 6.82 (1H, d, J=16.9Hz),                                (yellow crystal)                                                                            7.02 to 7.29 (5H, m), 8.03 (2H, d,                                            J=8.8Hz), 8.31 (2H, d, J=8.8Hz)                            32   (E)-4-{3-[1-(3-                                                                        418  1.49 to 1.70 (2H, m), 1.70 to 1.87                              trifluoromethyl-                                                                       (M.sup.+)                                                                          (2H, m), 2.00 to 2.16 (2H, m),                                  benzyl)piperi-                                                                              2.22 to 2.40 (1H, m), 2.85 to 2.97                              din-4-yl]pro- (2H, m), 3.57 (2H, s), 6.83 (1H,                                penoyl}nitro- d, J=15.9Hz), 7.09 (1H, dd, J=                                  benzene (brown                                                                              15.9Hz, 6.7Hz), 7.37 to 7.48 (1H,                               liquid)       m), 7.48 to 7.58 (2H, m), 7.60                                                (1H, s), 8.04 (2H, d, J=9.2Hz),                                               8.31 (2H, d, J=9.2Hz)                                      33   (E)-4-{3-[1-(4-                                                                        375  1.48 to 1.70 (2H, m), 1.75 to 1.87                              cyanobenzyl)-                                                                          (M.sup.+)                                                                          (2H, m), 2.03 to 2.17 (2H, m),                                  piperidin-4-  2.23 to 2.40 (1H, m), 2.82 to 2.97                              yl]propenoyl}-                                                                              (2H, m), 3.56 (2H, s), 6.83 (1H,                                nitrobenzene  d, J=15.4Hz), 7.08 (1H, dd,                                     (yellow crystal)                                                                            J=15.4Hz, 6.6Hz), 7.46 (2H, d,                                                J=8.1Hz), 7.61 (2H, d, J=8.1Hz),                                              8.04 (2H, d, J=8.8Hz), 8.32 (2H,                                              d, 8.8hz)                                                  34   (E)-4-{3-[1-(3-                                                                        375  1.47 to 1.70 (2H, m), 1.75 to 1.89                              cyanobenzyl)-                                                                          (M.sup.+)                                                                          (2H, m), 2.02 to 2.18 (2H, m),                                  piperidin-4-  2.22 to 2.44 (1H, m), 2.82 to                                   yl]propenoyl}-                                                                              2.96 (2H, m), 3.59 (2H, s), 6.84                                nitrobenzene  (1H, d, J=15.4Hz), 7.09 (1H, dd,                                (brown liquid)                                                                              J=15.4Hz, 6.6Hz), 7.37 to 7.50                                                (1H, m), 7.50 to 7.62 (2H, m),                                                7.66 (1H, s), 8.05 (2H, d,                                                    J=8.8Hz), 8.32 (2H, d, J=8.8Hz)                            35   (E)-4-{3-[1-(1-                                                                        400  1.46 to 1.66 (2H, m), 1.71 to 1.85                              naphthylmethyl)-                                                                       (M.sup.+)                                                                          (2H, m), 2.04 to 2.22 (2H, m),                                  piperidin-4-  2.22 to 2.40 (1H, m), 2.93 to 3.07                              yl]propenoyl}-                                                                              (2H, m), 3.91 (2H, s), 6.80 (1H,                                nitrobenzene  d, J=16.3Hz), 7.07 (1H, dd, J=                                  (brown liquid)                                                                              16.3Hz, 6.6Hz), 7.37 to 7.55 (4H,                                             m), 7.74 to 7.89 (2H, m), 8.02                                                (2H, d, J=8.8Hz), 8.30 (3H, d,                                                8.8Hz)                                                     36   (E)-4-{3-[1-(β-                                                                   364  1.39 (3H, d, J=6.6Hz), 1.43 to                                  phenethyl)piper-                                                                       (M.sup.+)                                                                          2.13 (6H, m), 2.13 to 2.32 (1H,                                 idin-4-yl]pro-                                                                              m), 2.81 to 2.93 (1H, m), 3.04 to                               penoyl}nitro- 3.17 (1H, m), 3.46 (1H, q, J=                                   benzene (reddish                                                                            6.6Hz), 6.79 (1H, d, J=15.4Hz),                                 brown liquid) 7.06 (1H, dd, J=15.4Hz, 6.6Hz),                                               7.17 to 7.39 (5H, m), 8.02 (2H, d,                                            J=8.8Hz), 8.30 (2H, d, J=8.8Hz)                            37   (E)-4-{3-[1-(3-                                                                        352  1.49 to 1.68 (2H, m), 1.74 to 1.88                              pyridylmethyl)-                                                                        (CI) (2H, m), 2.01 to 2.16 (2H, m),                                  piperidiin-4-                                                                          (M.sup.+ +1)                                                                       2.22 to 2.39 (1H, m), 2.83 to 2.99                              yl]propenoyl}-                                                                              (2H, m), 3.54 (2H, s), 6.83 (1H,                                nitrobenzene  d, J=15.9Hz), 7.08 (1H, dd, J=15.9                              (reddish brown                                                                              Hz, 6.7Hz), 7.21 to 7.30 (1H, m),                               crystal)      7.63 to 7.72 (1H, m), 8.04 (2H, d,                                            J=9.2Hz), 8.31 (2H, d, J=9.2Hz),                                              8.46 to 8.58 (2H, m)                                       38   (E)-4-{3-[1-(6-                                                                        366  1.53 to 1.72 (2H,m), 1.74 to 1.86                               methyl-2-pyridyl-                                                                      (CI) (2H, m), 2.09 to 2.24 (2H, m),                                  methyl)piperidin-                                                                      (M.sup.+ +1)                                                                       2.24 to 2.39 (1H, m), 2.55 (3H,                                 4-yl]propenoyl}-                                                                            s), 2.93 to 3.03 (2H, m), 3.65                                  nitrobenzene  (2H, s), 6.83 (1H, d, J=15.3Hz),                                (yellowish    7.03 (1H, d, J=7.9Hz), 7.09 (1H,                                brown crystal)                                                                              dd, J=15.3Hz, 6.7Hz), 7.55 (1H, t,                                            J=7.9Hz), 8.04 (2H, d, J=9.2Hz),                                              8.31 (2H, d, J=9.2Hz)                                      39   (E)-4-{3-[1-(2-                                                                        357  1.54 to 1.66 (2H, m), 1.76 to 1.85                              thienylmethyl)-                                                                        (CI) (2H, m), 2.03 to 2.15 (2H, m),                                  piperidin-4-                                                                           (M.sup.+ +1)                                                                       2.23 to 2.36 (1H, m), 2.96 to 3.04                              yl]propenoyl}-                                                                              (2H, m), 3.75 (2H, s), 6.82 (1H,                                nitrobenzene  d, J=15.6Hz), 6.99 to 7.03 (1H,                                 (yellow crystal)                                                                            m), 7.03 to 7.06 (1H, m), 7.08                                                (1H, dd, J=15.6Hz, 6.4Hz), 7.24                                               (1H, d, J=6.4Hz), 8.02 (2H, d,                                                J=8.8Hz), 8.31 (2H, d, J=8.8Hz)                            40   (E)-4-{3-[1-(3,4-                                                                      394  1.48 to 1.67 (2H, m), 1.74 to 1.87                              methylenedioxy-                                                                        (M.sup.+)                                                                          (2H, m), 1.96 to 2.11 (2H, m),                                  benzyl)piperi-                                                                              2.20 to 2.37 (1H, m), 2.88 to 3.00                              din-4-yl]pro- (2H, m), 3.43 (2H, s), 5.94 (2H,                                penoyl}nitro- s), 6.74 (2H, s), 6.82 (1H, d,                                  benzene (pale J=15.9Hz), 6.85 (1H, s), 7.08 (1H,                              yellow crystal)                                                                             dd, J=15.9Hz, 6.7Hz), 8.03 (2H,                                               d, J=9.2Hz), 8.31 (2H, d, J=9.2Hz)                         41   (E)-4-{3-[1-(3,4-                                                                      409  1.49 to 1.72 (2H, m), 1.72 to 1.84                              ethylenedioxy-                                                                         (CI) (2H, m), 1.95 to 2.11 (2H, m),                                  benzyl)piperi-                                                                         (M.sup.+ +1)                                                                       2.20 to 2.36 (1H, m), 2.89 to 2.99                              din-4-yl]pro- (2H, m), 3.41 (2H, s), 4.25 (4H,                                penoyl}nitro- s), 6.81 (1H, d, J=15.3Hz), 6.79                                benzene (brown                                                                              to 6.84 (3H, m), 7.08 (1H, dd,                                  liquid)       J=15.3Hz, 6.7Hz), 8.03 (2H, d,                                                J=9.2Hz), 8.31 (2H, d, J=8.8Hz)                            42   (E)-4-{3-[1-(2,3-                                                                      410  1.46 to 1.66 (2H, m), 1.73 to 1.85                              dimethoxybenz-                                                                         (M.sup.+)                                                                          (2H, m), 2.02 to 2.18 (2H, m),                                  yl)piperidin-4-                                                                             2.18 to 2.37 (1H, m), 2.94 to 3.03                              yl]propenoyl}-                                                                              (2H, m), 3.57 (2H, s), 3.83 (3H,                                nitrobenzene  s), 3.87 (3H, s), 6.80 (1H, d,                                  (brown liquid)                                                                              J=15.9Hz), 6.80 to 6.86 (1H, m),                                              6.95 to 7.00 (2H, m), 7.07 (1H,                                               dd, J=15.3Hz, 6.7Hz), 8.03 (2H, d,                                            J=9.2Hz), 8.31 (2H, d, J=9.2Hz)                            __________________________________________________________________________

Reference Examples 43 to 56

In the same manner as in Reference example 10, the following compoundswere obtained.

    __________________________________________________________________________    Refer-                                                                        ence                                                                          example                                                                            Compound Mass                                                            No.  (characteristics)                                                                      (m/z)                                                                              NMR (δ, CDCl.sub.3)                                  __________________________________________________________________________    43   4-{3-[1-(2-                                                                            340  1.19 to 1.40 (3H, m), 1.54 to 1.78                              fluorobenzyl)-                                                                         (M.sup.+)                                                                          (4H, m), 1.91 to 2.09 (2H, m),                                  piperidin-4-  2.77 to 2.96 (4H, m), 3.57 (2H,                                 yl]propanoyl]-                                                                              s), 4.09 (2H, s, br), 6.63 (2H, d,                              aniline (pale J=8.8Hz), 6.95 to 7.13 (2H, m),                                 yellow crystal)                                                                             7.16 to 7.29 (1H, m), 7.34 to 7.43                                            (1H, m), 7.80 (2H, d, J=8.8Hz)                             44   4-{3-[1-(4-                                                                            356  1.23 to 1.42 (3H, m), 1.63 to 1.75                              chlorobenzyl)-                                                                         (M.sup.+)                                                                          (4H, m), 1.85 to 2.04 (2H, m),                                  piperidin-4-  2.81 to 2.95 (4H, m), 3.39 to 3.54                              yl]propanoyl}-                                                                              (2H, br), 4.09 (2H, br), 6.64 (2H,                              aniline (white                                                                              d), 7.23 to 7.33 (4H, m), 7.80                                  crystal)      (2H, d)                                                    45   4-{3-[1-(2-                                                                            352  (CDCl.sub.3 DMSO-d.sub.6) 1.38 to 1.59 (1H,                     methoxybenzyl)-                                                                        (M.sup.+)                                                                          m), 1.59 to 1.90 (6H, m), 2.38 to                               piperidin-4-  2.62 (2H, m), 2.86 (2H, t, J=                                   yl]propanoyl}-                                                                              7.3Hz), 3.16 to 3.33 (2H, m), 3.85                              aniline.HCl   (3H, s), 4.01 (2H, s, br), 4.69                                 salt (yellowish                                                                             (2H, s, br), 6.64 (2H, d, J=                                    brown crystal)                                                                              8.6Hz), 6.90 to 7.03 (2H, m), 7.30                                            to 7.40 (1H, m), 7.54 to 7.63 (1H,                                            m), 7.74 (2H, d, J=8.6Hz)                                  46   4-{3-[1-(3-                                                                            428  1.20 to 1.39 (3H, m), 1.59 to 1.74                              benzyloxybenz-                                                                         (M.sup.+)                                                                          (4H, m), 1.85 to 2.00 (2H, m),                                  yl)piperidin-4-                                                                             2.79 to 3.01 (4H, m), 3.46 (2H,                                 yl]propanoyl}-                                                                              s), 4.09 (2H, s, br), 5.06 (2H,                                 aniline (brown                                                                              s), 6.64 (2H, d, J=8.6Hz), 6.82 to                              liquid)       6.91 (2H, m), 7.18 (1H, s), 7.19                                              to 7.27 (1H, m), 7.31 to 7.48 (5H,                                            m), 7.80 (2H, d, J=8.6Hz)                                  47   4-{3-[1-(3-                                                                            336  1.19 to 1.40 (3H, m), 1.53 to 1.77                              methylbenzyl)-                                                                         (M.sup.+)                                                                          (4H, m), 1.84 to 2.01 (2H, m),                                  piperidin-4-  2.34 (3H, s), 2.76 to 2.96 (4H,                                 yl]propanoyl}-                                                                              m), 3.44 (2H, s), 4.11 (2H, s,                                  aniline (yellow                                                                             br), 6.63 (2H, d, J=8.8Hz), 7.00                                crystal)      to 7.26 (4H, m), 7.80 (2H, d,                                                 J=8.8Hz)                                                   48   4-{3-[1-(3-tri-                                                                        390  1.17 to 1.42 (3H, m), 1.56 to 1.80                              fluorobenzyl)-                                                                         (M.sup.+)                                                                          (4H, m), 1.88 to 2.04 (2H, m),                                  piperidin-4-  2.79 to 2.94 (4H, m), 3.51 (2H,                                 yl]propanoyl}-                                                                              s), 4.12 (2H, s, br), 6.64 (2H, d,                              aniline (yellow                                                                             J=8.6Hz), 7.37 to 7.45 (1H, m),                                 crystal)      7.45 to 7.56 (2H, m), 7.57 (1H,                                               s), 7.80 (1H, d, J=8.6Hz)                                  49   4-{3-[1-(4-                                                                            347  (CDCl.sub.3 -DMSO-d.sub.6) 1.13 to 1.40 (3H,                    cyanobenzyl)-                                                                          (M.sup.+)                                                                          m), 1.51 to 1.78 (4H, m), 1.87 to                               piperidin-4-  2.05 (2H, m), 2.69 to 2.92 (4H,                                 yl]propanoyl}-                                                                              m), 3.52 (2H, s), 4.98 (2H, s,                                  aniline (pale br), 6.63 (2H, d, J=8.8Hz), 7.46                                brown crystal)                                                                              (2H, d, J=8.1Hz), 7.60 (2H, d,                                                J=8.1Hz), 7.74 (2H, d, J=8.8Hz)                            50   4-{3-[1-(2-                                                                            372  (CDCl.sub.3 -DMSO-d.sub.6) 1.28 to 1.50 (1H,                    naphthylmethyl)-                                                                       (M.sup.+)                                                                          m), 1.50 to 1.81 (6H, m), 2.10 to                               piperidin-4-  2.50 (2H, m), 2.83 (2H, t, J=                                   yl]propanoyl}-                                                                              7.3Hz), 2.93 to 3.27 (2H, m), 3.81                              aniline.HCl   to 4.27 (2H, br), 5.29 (2H, s),                                 salt (yellowish                                                                             6.61 (2H, d, J=8.8Hz), 7.40 to                                  brown crystal)                                                                              7.59 (4H, m), 7.69 (2H, d, J=                                                 8.8Hz), 7.76 to 7.92 (2H, m), 8.23                                            to 8.34 (1H, m)                                            51   4-{3-[1-(2-                                                                            323  1.20 to 1.45 (3H, m), 1.50 to 1.80                              pyridylmethyl)-                                                                        (M.sup.+)                                                                          (4H, m), 1.95 to 2.15 (2H, m),                                  piperidin-4-  2.80 to 3.00 (4H, m), 3.64 (2H,                                 yl]propanoyl}-                                                                              s), 4.09 (2H, s, br), 6.64 (2H, d,                              aniline (yellow                                                                             J=8.8Hz), 7.10 to 7.20 (1H, m),                                 crystal)      7.38 to 7.47 (1H, m), 7.60 to 7.69                                            (1H, m), 7.81 (2H, d, J=8.8Hz),                                               8.52 to 8.60 (1H, m)                                       52   4-{3-[1-(3-                                                                            323  1.13 to 1.40 (3H, m), 1.54 to 1.78                              pyridylmethyl)-                                                                        (M.sup.+)                                                                          (4H, m), 1.84 to 2.03 (2H, m),                                  piperidin-4-  2.75 to 2.93 (4H, m), 3.48 (2H,                                 yl]propanoyl}-                                                                              s), 4.19 (2H, s, br), 6.64 (2H, d,                              aniline (pale J=8.8Hz), 7.19 to 7.30 (1H, m),                                 yellow crystal)                                                                             7.62 to 7.71 (1H, m), 7.80 (2H, d                                             J=8.8Hz), 8.45 to 8.58 (2H, m)                             53   4-{3-[1-(4-                                                                            323  1.18 to 1.41 (3H, m), 1.50 to 1.79                              pyridylmethyl)-                                                                        (M.sup.+)                                                                          (4H, m), 1.89 to 2.07 (2H, m),                                  piperidin-4-  2.73 to 2.93 (4H, m), 3.48 (2H,                                 yl]propanoyl}-                                                                              s), 4.10 (2H, s, br), 6.64 (2H, d,                              aniline (pale J=8.8Hz), 7.27 (2H, d, J=5.9Hz),                                yellow crystal)                                                                             7.81 (2H, d, J=8.8Hz), 8.52 (2H,                                              d, J=5.9Hz)                                                54   4-{3-[1-(6-                                                                            338  1.26 to 1.46 (3H, m), 1.62 to 1.76                              methyl-4-pyrid-                                                                        (CI) (4H, m), 1.97 to 2.13 (2H, m),                                  ylmethyl)piper-                                                                        (M.sup.+ +1)                                                                       2.54 (3H, s), 2.83 to 2.95 (4H,                                 idin-4-yl]pro-                                                                              m), 3.61 (2H, s), 4.10 (2H, s,                                  panoyl}aniline                                                                              br), 6.64 (2H, d, J=9.2Hz), 7.00                                (yellow crystal)                                                                            (1H, d, J=7.3Hz), 7.21 to 7.30                                                (1H, m), 7.49 to 7.58 (1H, m),                                                7.81 (2H, d, J=9.2Hz)                                      55   4-{3-[1-(3,4-                                                                          380  1.24 to 1.38 (3H, m), 1.61 to 1.74                              ethylenedioxy-                                                                         (M.sup.+)                                                                          (4H, m), 1.83 to 1.97 (2H, m),                                  benzyl)piperi-                                                                              2.81 to 2.93 (4H, m), 3.37 (2H,                                 din-4-yl]pro- s), 4.10 (2H, s, br), 4.24 (4H,                                 panoyl}aniline                                                                              s), 6.64 (2H, d, J=9.2Hz), 6.78 to                              (brown liquid)                                                                              6.82 (3H, m), 7.80 (2H, d, J=                                                 9.2Hz)                                                     56   4-{3-[1-(2,3-                                                                          382  1.20 to 1.37 (3H, m), 1.62 to 1.74                              dimethoxybenz-                                                                         (M.sup.+)                                                                          (4H, m), 1.94 to 2.07 (2H, m),                                  yl)piperidin-4-                                                                             2.82 to 2.97 (4H, m), 3.54 (2H,                                 yl]propanoyl}-                                                                              s), 4.82 (3H, s), 3.86 (3H, s),                                 aniline (brown                                                                              4.12, (2H, s, br) 6.64 (2H, d, J=                               liquid)       8.6Hz), 6.82 (1H, d, J=7.3Hz),                                                6.94 to 7.05 (2H, m), 7.80 (2H, d,                                            J=8.6Hz)                                                   __________________________________________________________________________

Reference Examples 57 to 66

In the same manner as in Reference examples 13, 14, 15 and 16, thefollowing compounds were obtained.

    __________________________________________________________________________    Refer-                                                                        ence                                                                          example                                                                            Compound Mass                                                            No.  (characteristics)                                                                      (m/z)                                                                              NMR (δ, (CDCl.sub.3)                                 __________________________________________________________________________    57   N-trifluoroace-                                                                        403  2.39 to 2.49 (2H, m), 2.49 to 2.66                              tyl-4-[(1-benzyl-                                                                      (M.sup.+ +1)                                                                       (4H, m), 2.87 to 3.00 (2H, m),                                  4-piperidinylid-                                                                            3.54 (2H, s), 6.63 (1H, s), 7.17                                ene)acetyl]ani-                                                                             to 7.41 (5H, m), 7.69 (2H, d,                                   line (pale yel-                                                                             J=8.5Hz), 7.97 (2H, d, J=8.5Hz),                                low crystal)  8.38 (1H, br)                                              58   N-trifluoroace-                                                                        405  1.25 to 1.47 (2H, m), 1.63 to 1.79                              tyl-4-[(1-benzyl-                                                                      (M.sup.+ +1)                                                                       (2H, m), 1.87 to 2.08 (3H, m),                                  piperidin-4-yl)-                                                                            2.76 to 2.94 (4H, m), 3.49 (2H,                                 acetyl]aniline                                                                              s), 7.18 to 7.37 (5H, m), 7.70                                  (pale yellow  (2H, d, J=9.1Hz), 7.97 (2H, d,                                  crystal)      J=9.1Hz)                                                   59   N-acetyl-4-[(1-                                                                        397  1.56 to 1.90 (4H, m), 2.23 (3H,                                 benzyl-4-hydroxy-                                                                      (M.sup.+ +1)                                                                       s), 2.40 to 2.69 (4H, m), 3.09                                  piperidin-4-yl)-                                                                            (2H, s), 3.52 (2H, s), 3.96 (3H,                                acetyl]-2-meth-                                                                             s), 4.10 (1H, s), 6.93 (1H, d,                                  oxyaniline (pale                                                                            J=8.5Hz), 7.17 to 7.40 (5H, m),                                 yellow crystal)                                                                             7.67 to 7.80 (2H, m), 8.99 (1H, d,                                            J=2.4Hz)                                                   60   N-acetyl-4-[(1-                                                                        379  2.22 (3H, s), 2.37 to 2.48 (2H,                                 benzyl-4-piperi-                                                                       (M.sup.+ +1)                                                                       m), 2.48 to 2.65 (4H, m), 2.88 to                               dinylidene)ace-                                                                             2.99 (2H, m), 3.53 (2H, s), 3.94                                tyl]-2-methoxy-                                                                             (3H, s), 6.65 (1H, s), 6.934 (1H,                               aniline (yellow                                                                             d, J=8.5Hz), 7.20 to 7.39 (5H, m),                              crystal)      7.67 to 7.80 (2H, m), 8.97 (1H, d,                                            J=2.4Hz)                                                   61   N-acetyl-4-[(1-                                                                        381  1.30 to 1.44 (2H, m), 1.60 to 1.78                              benzylpiperidin)-                                                                      (M.sup.+ +1)                                                                       (3H, m), 1.93 to 2.06 (2H, m),                                  4-yl)acetyl]-2-                                                                             2.22 (3H, s), 2.79 to 2.91 (4H,                                 methoxyaniline                                                                              m), 3.49 (2H, s), 3.94 (3H, s),                                 (yellowish    6.92 (1H, d, J=8.8Hz), 7.20 to                                  brown liquid) 7.36 (5H, m), 7.72 (1H, dd, J=                                                8.8Hz, 2.0Hz), 7.76 (1H, s, br),                                              8.98 (1H, d, J=2.0Hz)                                      62   4-[(1-benzyl-                                                                          339  (CDCl.sub.3 -DMSO-d.sub.6) 1.66 to 1.72 (2H,                    piperidin-4-                                                                           (M.sup.+ +1)                                                                       m), 1.72 to 1.96 (2H, m), 2.09 to                               yl)acetyl]-2- 2.23 (1H, m), 2.88 to 3.07 (4H,                                 methoxyaniline.                                                                             m), 3.29 to 3.40 (2H, m), 3.99                                  2HCl salt (pale                                                                             (3H, s), 4.27 (2H, d, J=4.9Hz),                                 brown crystal)                                                                              7.20 (1H, d, J=8.8Hz), 7.39 to                                                7.46 (3H, m), 7.60 to 7.72 (2H,                                               m), 7.92 (1H, dd, J=8.8Hz, 2.0Hz),                                            7.98 (1H, d, J=2.0Hz), 10.82 (1H,                                             br)                                                        63   N-acetyl-4-[(1-                                                                        382  1.58 to 1.87 (4H, m), 2.82 (3H,                                 benzyl-4-hydroxy-                                                                      (M.sup.+                                                                           s), 2.40 to 2.71 (4H, m), 3.05                                  piperidin-4-yl)-                                                                       -18) (2H, s), 3.52 (2H, s), 3.80 (1H,                                acetyl]-2-chloro-                                                                           s), 7.20 to 7.36 (5H, m), 7.78 to                               aniline (pale 7.90 (2H, m), 7.98 (1H, d,                                      brown liquid) J=1.8Hz), 8.56 (1H, d, J=9.1Hz)                            64   Mixture of N-ace-                                                                      383  2.08 to 2.22, 2.40 to 2.65, 2.88                                tyl-4-[()1-benzyl-                                                                     (M.sup.+ +1)                                                                       to 3.04 and 3.30 to 3.64 (total                                 4-piperidinyl-                                                                              10H), 2.28 (3H, s), 5.33 and 6.60                               idene-acetyl]-2-                                                                            (total 1H), 7.17 to 7.39 (5H, m),                               chloroaniline and                                                                           7.73 to 7.91 (2H, m), 7.96 to 8.03                              N-acetyl-4-[(1-                                                                             (1H, m), 8.49 to 8.57 (1H, m)                                   benzyl-1,2,5,6-                                                               tetrahydropyridin-                                                            4-yl)acetyl]-2-                                                               chloroaniline                                                                 (pale brown                                                                   liquid)                                                                  65   N-acetyl-4-[(1-                                                                        385  1.81 to 2.03 (2H, m), 2.03 to 2.35                              benzylpiperi-                                                                          (M.sup.+ +1)                                                                       (3H, m), 2.28 (3H, s), 2.59 to                                  din-4-yl)ace- 2.80 (2H, m), 2.88 to 2.99 (2H,                                 tyl]-2-chloro-                                                                              m), 3.34 to 3.53 (2H, m), 4.14                                  aniline.HCl   (2H, s), 7.40 to 7.50 (3H, m),                                  salt (pale yel-                                                                             7.57 to 7.68 (2H, m), 7.77 to 7.88                              low crystal)  (2H, m), 7.95 (1H, d, J=1.8Hz),                                               8.55 (1H, d, J=9.1Hz)                                      66   4-[(1-benzyl-                                                                          343  (CDCl.sub.3 -DMSO-d.sub.6) 1.82 to 2.00 (2H,                    piperidin-4-                                                                           (M.sup.+ +1)                                                                       m), 2.00 to 2.32 (3H, m), 2.61 to                               yl)acetyl]-2- 2.90 (2H, m), 2.84 (2H, d, J=                                   chloroaniline.                                                                              6.1Hz), 3.33 to 3.53 (2H, m), 4.15                              2HCl salt (pale                                                                             (2H, d, J=4.9Hz), 6.89 (1H, d,                                  brown solid)  J=8.6Hz), 7.35 to 7.52 (3H, m),                                               7.52 to 7.74 (3H, m), 7.83 (1H, d,                                            J=2.4Hz), 12.22 (1H, br)                                   67   N-acetyl-4-[(1-                                                                        397  1.61 to 1.78 (4H, m), 2.24 (3H,                                 benzyl-4-hydroxy-                                                                      (M.sup.+ +1)                                                                       s), 2.39 to 2.91 (4H, m), 3.08                                  piperidin-4-  (2H, s), 3.53 (2H, s), 3.81 (1H,                                yl)acetyl]-3- s, br), 3.88 (3H, s), 6.60 (1H,                                 methoxyaniline                                                                              dd, J=9.2Hz, 2.4Hz), 7.16 to 7.40                               (pale yellow  (5H, m), 7.80 (1H, d, J=9.2Hz),                                 liquid)       8.43 (1H, d, J=2.4Hz), 11.95 (1H,                                             s, br)                                                     68   N-acetyl-4-[(1-                                                                        381  1.27 to 1.46 (2H, m), 1.64 to 1.78                              benzylpiperidin-                                                                       (M.sup.+ +1)                                                                       (2H, m), 1.83 to 2.09 (3H, m),                                  4-yl)acetyl]-3-                                                                             2.23 (3H, s), 2.75 to 2.94 (2H,                                 methoxyaniline                                                                              m), 2.84 (2H, d, J=6.7Hz), 3.49                                 (pale yellow  (2H, s), 3.87 (3H, s), 6.60 (1H,                                liquid)       dd, J=9.2Hz, 2.4Hz), 7.13 to 7.40                                             (5H, m), 7.81 (1H, d, J=8.6Hz),                                               8.42 (1H, d, J=2.4Hz), 12.15 (1H,                                             s, br)                                                     69   4-[(1-benzyl-                                                                          339  (CDCl.sub.3 -DMSO-d.sub.6) 1.84 to 2.33 (5H,                    piperidin-4-                                                                           (M.sup.+ +1)                                                                       m), 2.74 to 2.98 (2H, m), 2.87                                  yl)acetyl]-3- (2H, d, J=6.1Hz), 3.31 to 3.50                                  methoxyaniline.                                                                             (2H, m), 3.82 (3H, s), 4.21 (2H,                                2HCl salt     d, J=4.9Hz), 6.38 (1H, dd, J=                                   (reddish brown                                                                              9.2Hz, 2.4Hz), 6.52 (1H, d, J=                                  solid)        2.4Hz), 7.28 to 7.52 (3H, m), 7.52                                            to 7.83 (3H, m), 11.70 (1H, br)                            __________________________________________________________________________

EFFECTS OF THE INVENTION

The compound having the formula (I) of the present invention hasexcellent selective inhibiting activities to both ofacetylcholinesterase and A type monoamine oxidase, and is extremelyuseful as an antidepressant and an agent for curing senile dementia.

As an administration form for such purposes, there may be mentioned, forexample, oral administration by a tablet, a capsule, a granule, apowder, syrup, etc. or parenteral administration by an intravenousinjection, an intramuscular injection, a suppository, etc. The dosevaries depending on age, body weight, symptoms, an administration form,an administration time, etc., but it is generally about 1 to 1,000 mgper day in one dose or divided doses to an adult.

Test example 1. Acetylcholinesterase-inhibiting activity

As an enzyme source, a crude synaptosome fraction of a rat cerebrum wasused. The crude synaptosome fraction was prepared by homogenizing a ratcerebrum in a 0.32M sucrose solution and, after centrifugal operation,suspending it in a 0.1M phosphate buffer.

The activity of acetylcholinesterase was measured by a partiallymodified method of the method of Ellman et. al. (Ellman, G. L. et al.,Biochem. Pharmacol., 7, 88 (1961)). That is, to the crude synaptosomefraction of the rat cerebrum suitably diluted with a 0.1M phosphatebuffer were added each compound to be tested,5,5'-dithiobis(2-nitrobenzoic acid) (hereinafter referred to as DTNB)and acetylthiocholine as a substrate, and the mixture was incubated at25° C. for a predetermined time. Subsequently, the amount of yellowanions formed by reaction of acetylthiocholine and DTNB was measured asabsorbance at 410 nm to determine the activity of acetylcholinesterase.

Enzyme activity-inhibiting rates were calculated from absorbances in thepresence of the compounds to be tested having various concentrationsbased on absorbances in the absence of the compounds to be tested, withabsorbance when reaction was carried out in the absence of the substratebeing defined as blank. IC₅₀ values were calculated by Hill analysis.

Test example 2. Butyrylcholinesterase-inhibiting activity

As an enzyme source, a rat serum was used.

The activity of butyrylcholinesterase was measured by a partiallymodified method of the above method of Ellman et. al. That is, to therat serum suitably diluted with a 0.1M phosphate buffer were added eachcompound to be tested, DTNB and butyrylthiocholine as a substrate, andthe mixture was incubated at 25° C. for a predetermined time.Subsequently, the amount of yellow anions formed by reaction ofbutyrylthiocholine and DTNB was measured as absorbance at 410 nm todetermine the activity of butyrylcholinesterase.

Enzyme activity-inhibiting rates were calculated from absorbances in thepresence of the compounds to be tested having various concentrationsbased on absorbances in the absence of the compounds to be tested, withabsorbance when reaction was carried out in the absence of the substratebeing defined as blank. IC₅₀ values were calculated by Hill analysis.

Test example 3. A type and B type monoamine oxidase-inhibiting activity

As an enzyme source, a rat cerebrum homogenized in a 0.1M phosphatebuffer was used.

The activities of monoamine oxidases were measured by a partiallymodified method of the method of Da Prada et al. (Da Prada, M. et al.,J. Pharmacol. Exp. Ther., 248 (1), 400 (1989)). That is, the ratcerebrum homogenate suitably diluted with a 0.1M phosphate buffer andeach compound to be tested were preincubated at 37° C. for 30 minutes.Then, a substrate labeled with ¹⁴ C (5-hydroxy-tryptamine (5-HT) havinga final concentration of 200 μM was used in measurement of the activityof A type monoamine oxidase, and β-phenylethylamine (β-PEA) having afinal concentration of 20 μM was used in measurement of the activity ofB type monoamine oxidase) was added to the preincubated mixture, and themixture was incubated at 37° C. for a predetermined time. After thereaction was terminated by adding hydrochloric acid (finalconcentration; 1.2M), the reaction mixture and a predetermined amount ofan organic solvent (diethyl ether was used in measurement of theactivity of A type monoamine oxidase, and heptane was used inmeasurement of the activity of B type monoamine oxidase) were vigorouslystirred so that deaminated metabolites were extracted into the organiclayer. After the mixture was separated into two layers bycentrifugation, a part of the organic layer was mixed with liquidscintillation cocktail. Radioactivity extracted into the organic layerwas measured by a liquid scintillation counter to calculate the enzymeactivity.

Inhibiting rates were calculated from enzyme activities in the presenceof the compounds to be tested having various concentrations based onenzyme activities in the absence of the compounds to be tested, withabsorbance when reaction was carried out in the absence of thehomogenate being defined as blank. IC₅₀ values were calculated by Hillanalysis.

The results of Test examples 1 to 3 are shown in Table 3.

                                      TABLE 3                                     __________________________________________________________________________            IC.sub.50 value (M)                                                                           Inhibition                                                                          Inhibition                                              Inhibition of                                                                        Inhibition of                                                                          of A type                                                                           of B type                                       Compound to                                                                           acetylcholin-                                                                        butyrylcholin-                                                                         monoamine                                                                           monoamine                                       be tested                                                                             esterase                                                                             esterase oxidase                                                                             oxidase                                         __________________________________________________________________________    Compound of                                                                           3.3 × 10.sup.-9                                                                >10.sup.-5                                                                             1.6 × 10.sup.-6                                                               >10.sup.-5                                      Example 1                                                                     Compound of                                                                           3.6 × 10.sup.-9                                                                >10.sup.-5                                                                             8.9 × 10.sup.-7                                                               >10.sup.-5                                      Example 2                                                                     Compound of                                                                           3.1 × 10.sup.-9                                                                >10.sup.-5                                                                             2.2 × 10.sup.-7                                                               >10.sup.-5                                      Example 6                                                                     Compound of                                                                           2.0 × 10.sup.-9                                                                >10.sup.-5                                                                             8.5 × 10.sup.-8                                                               >10.sup.-5                                      Example 8                                                                     Compound of                                                                           1.4 × 10.sup.-9                                                                >10.sup.-5                                                                             1.4 × 10.sup.-6                                                               >10.sup.-5                                      Example 9                                                                     Compound of                                                                           1.1 × 10.sup.-9                                                                >10.sup.-5                                                                             3.2 × 10.sup.-7                                                               >10.sup.-5                                      Example 10                                                                    Compound of                                                                           2.0 × 10.sup.-8                                                                >10.sup.-5                                                                             6.0 × 10.sup.-7                                                               >10.sup.-5                                      Example 21                                                                    Compound of                                                                           7.3 × 10.sup.-9                                                                >10.sup.-5                                                                             8.1 × 10.sup.-7                                                               >10.sup.-5                                      Example 22                                                                    Compound of                                                                           2.5 × 10.sup.-7                                                                >10.sup.-5                                                                             3.4 × 10.sup.-7                                                               6.8 × 10.sup.-6                           Example 25                                                                    Compound of                                                                           1.5 × 10.sup.-7                                                                >10.sup.-5                                                                             5.6 × 10.sup.-8                                                               >10.sup.-5                                      Example 26                                                                    Compound of                                                                           1.7 × 10.sup.-8                                                                >10.sup.-5                                                                             8.5 × 10.sup.-8                                                               >10.sup.-5                                      Example 53                                                                    Compound of                                                                           2.7 × 10.sup.-7                                                                >10.sup.-5                                                                             3.5 × 10.sup.-8                                                               >10.sup.-5                                      Example 87                                                                    Compound of                                                                           3.3 × 10.sup.-7                                                                >10.sup.-5                                                                             2.5 × 10.sup.-7                                                               2.1 × 10.sup.-6                           Example 88                                                                    Compound of                                                                           2.0 × 10.sup.-7                                                                >10.sup.-5                                                                             4.2 × 10.sup.-7                                                               7.2 × 10.sup.-6                           Example 93                                                                    Compound A                                                                            7.3 × 10.sup.-9                                                                3.9 × 10.sup.-6                                                                  >10.sup.-5                                                                          >10.sup.-5                                      Compound B                                                                            >10.sup.-5                                                                           >10.sup.-5                                                                             1.6 × 10.sup.-7                                                               >10.sup.-5                                      __________________________________________________________________________     Compound A: 1benzyl-4-[(5,6dimethoxy-1-indanon)-2-yl]methylpiperidine         Compound B: 4(4-cyanoanilino)-5,6-dihydro-7H-cyclopenta-[d]pyrimidine    

We claim:
 1. A pyrimidine compound of the formula (I): ##STR146##wherein R¹ and R² each represent a hydrogen atom, a halogen atom, anamino group, a nitro group, an alkyl group, a lower alkoxy group or alower alkoxycarbonyl group, or R¹ and R² are bonded together to form aC₃ -₆ alkylene group, and said alkyl group and alkylene group beingunsubstituted or substituted by a halogen, hydroxy, a lower alkoxy, alower alkenyloxy, an aryloxy, an aralkyloxy or an acyloxy.R³ representsan aralkyl group or a C₁ -C₄ alkyl group substituted by a heteroaromatic ring, the hetero aromatic ring comprising a 5- or 6-memberedaromatic heteromonocyclic group having one or two hetero atoms selectedfrom the group consisting of nitrogen, oxygen and sulfur, or a fusedaromatic group comprising a benzene ring fused with said 5- or6-membered aromatic heteromonocyclic group, and the aryl portion of saidaralkyl group and said C₁ -C₄ alkyl group being unsubstituted orsubstituted by a halogen, amino, alkanoylamino, cyano, nitro, hydroxy, alower alkyl, a lower alkoxy, an aralkyloxy, an alkylenedioxy, ahalogeno-lower alkyl or a halogeno-lower alkoxy, R⁴ represents ahydrogen atom or an acyl group, R⁵ represents a hydrogen atom, a hydroxygroup or a lower alkoxy group, A represents ##STR147## where R⁶represents a hydrogen atom, a halogen atom, a lower alkyl group or alower alkoxy group, X represents --CH=, --CH=CH--(CH₂)_(p) --, --CH₂ --or --CH₂ CH₂ --(CH₂)_(p) --, Y represents =CH--(CH₂)_(p) --, --CH₂--(CH₂)_(p) --, a single bond or a double bond and p represents 0 or 1,. . . represents a single bond or a double bond, and when . . .represents a double bond or X represents --CH=, or Y represents a doublebond, R⁵ does not exist, and a salt thereof.
 2. The pyrimidine compoundand a salt thereof according to claim 1 which is represented by theformula (II): ##STR148## wherein R¹, R², R³, R⁴, R⁵, R⁶, X and . . .have the same meanings as defined above in claim
 1. 3. The pyrimidinecompound and a salt thereof according to claim 1 or 2, wherein R¹ and R²are bonded together to form a C₃₋₆ straight or branched alkylene group.4. The pyrimidine compound and a salt thereof according to claim 3,wherein the alkylene group formed by bonding R¹ and R² together is atrimethylene group or a tetramethylene group.
 5. The pyrimidine compoundand a salt thereof according to claim 1, or 2, wherein R¹ and R² are thesame or different and each represent a hydrogen atom, a fluorine atom, achlorine atom, a bromine atom or a C₁₋₇ straight or branched alkylgroup.
 6. The pyrimidine compound and a salt thereof according to claim5, wherein one of R¹ and R² is a C₁₋₄ alkyl group and the other is ahydrogen atom, a chlorine atom or a C₁₋₄ alkyl group.
 7. The pyrimidinecompound and a salt thereof according to claim 6, wherein R¹ is a C₁₋₄alkyl group and R² is a hydrogen atom or a C₁₋₄ alkyl group.
 8. Thepyrimidine compound and a salt thereof according to claim 1 or 2,wherein R³ is a benzyl group, a sec-phenethyl group, a fluorobenzylgroup, a chlorobenzyl group, a methoxybenzyl group, a cyanobenzyl group,a nitrobenzyl group, a 2-thienylmethyl group, a 2-furylmethyl group, a2-pyridylmethyl group or a 6-methyl-2-pyridylmethyl group.
 9. Thepyrimidine compound and a salt thereof according to claim 8, wherein R³is a benzyl group.
 10. The pyrimidine compound and a salt thereofaccording to claim 1 or 2, wherein R⁴ is a hydrogen atom or an acetylgroup.
 11. The pyrimidine compound and a salt thereof according to claim1 or 2, wherein R⁵ is a hydrogen atom.
 12. The pyrimidine compound and asalt thereof according to claim 2, wherein R⁶ is a hydrogen atom, achlorine atom, a fluorine atom or a methoxy group.
 13. The pyrimidinecompound and a salt thereof according to claim 2, wherein all of R⁴, R⁵and R⁶ are hydrogen atoms.
 14. The pyrimidine compound and a saltthereof according to claim 2, wherein X is --CH₂ --, --CH₂ CH₂ -- or--CH=CH-- and . . . is a single bond.
 15. The pyrimidine compound and asalt thereof according to claim 2, which is selected from the groupconsistingof(E)-N-(5,6-dimethylpyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]aniline,(E)-N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]aniline,N-(5,6,7,8-tetrahydroquinazolin-4-yl)-4-[3-(1-benzyl-piperidin-4-yl)propanoyl]aniline,N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-([1-(2-thienylmethyl)piperidin-4-yl]acetyl)aniline,N-(5-methylpyrimidin-4-yl)-4-{[1-(2-thienylmethyl)-piperidin-4-yl]acetyl}anilineand N-(5-ethylpyrimidin-4-yl)-4-[(1-benzylpiperidin-4-yl)acetyl]aniline.16. The pyrimidine compound and a salt thereof according to claim 2,wherein said compound isN-(5,6-dimethylpyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline.17. The pyrimidine compound and a salt thereof according to claim 2,wherein said compound isN-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline.18. The pyrimidine compound and a salt thereof according to claim 2,wherein said compound isN-(5-methylpyrimidin-4-yl)-4[(1-benzylpiperidin-4-yl)acetyl]aniline. 19.The pyrimidine compound and a salt thereof according to claim 2, whereinsaid compound isN-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(1-benzylpiperidin-4-yl)acetyl]aniline.20. The pyrimidine compound and a salt thereof according to claim 2,wherein said compound isN-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-{3-[1-(2-pyridylmethyl)piperidin-4-yl]propanoyl}aniline.21. The pyrimidine compound and a salt thereof according to claim 16,whereinR¹ and R² each represent a hydrogen atom, a halogen atom, anamino group, a nitro group, a C₁ -C₁₀ alkyl group, a C₁ -C₄ alkoxy groupor a C₂ -C₅ alkoxycarbonyl group or R¹ and R² are bonded together toform a C₃ -C₆ alkylene group, and said C₁ -C₁₀ alkyl group and said C₃-C₆ alkylene group being unsubstituted or substituted by a halogen,hydroxy, C₁ -C₄ alkoxy, C₃ -C₄ alkenyloxy, phenoxy, naphthoxy,benzyloxy, phenethyloxy, C₇ -C₈ aralkyloxy or C₁ -C₁₀ aliphatic acyloxy,R³ represents an aryl C₁ -C₄ alkyl group or a C₁ -C₄ alkyl groupsubstituted by a hetero aromatic ring, the hetero aromatic ringcomprising a 5- or 6-membered hetermonocyclic group having one or twohetero atoms selected from the group consisting of nitrogen, oxygen andsulfur, or a fused aromatic group comprising a benzene ring fused withsaid 5- or 6-membered aromatic heteromonocyclic group, and the arylportion of said aryl C₁ -C₄ alkyl group and said C₁ -C₄ alkyl groupwhich is substituted by said hetero aromatic ring being unsubstituted orsubstituted by a halogen, amino, C₁ -C₄ alkanoylamino, cyano, nitro,hydroxy, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, benzyloxy, phenethyloxy,naphthylmethoxy, C₇ -C₁₁ aralkyloxy, C₁ -C₂ alkylenedioxy, a halogeno-C₁-C₄ alkyl or a halogeno-C₁ -C₄ alkoxy, R⁴ represents a hydrogen atom ora C₁ -C₁₀ aliphatic acyl group, R⁵ represents a hydrogen atom, a hydroxygroup or a C₁ -C₄ alkoxy group, and R⁶ represents a hydrogen atom, ahalogen atom, a C₁ -C₄ alkyl group or a C₁ -C₄ alkoxy group.